GLP-1R agonists and uses thereof

ABSTRACT

The present disclosure provides compounds of Formula (III) 
     
       
         
         
             
             
         
       
         
         
           
             and pharmaceutical compositions thereof, for use in, e.g. treating type 2 diabetes mellitus, pre-diabetes, obesity, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and cardiovascular disease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. non-provisionalapplication Ser. No. 16/902,807, filed on Jun. 16, 2020, which is acontinuation application of International Patent Application No.PCT/CN2020/084203, filed on Apr. 10, 2020, which claims the benefit ofpriority under 35 U.S.C. 365(b) to International Patent Application No.PCT/CN2019/082381, filed on Apr. 12, 2019. The entire contents of theaforementioned applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Diabetes is a major public health concern because of its increasingprevalence and associated health risks. The disease is characterized byhigh levels of blood glucose resulting from defects in insulinproduction, insulin action, or both. Two major forms of diabetes arerecognized, Type 1 and Type 2. Type 1 diabetes (T1D) develops when thebody's immune system destroys pancreatic beta cells, the only cells inthe body that make the hormone insulin that regulates blood glucose. Tosurvive, people with Type 1 diabetes must have insulin administered byinjection or a pump. Type 2 diabetes mellitus (referred to generally asT2DM) usually begins with either insulin resistance or when there isinsufficient production of insulin to maintain an acceptable glucoselevel.

Currently, various pharmacological approaches are available for treatinghyperglycemia and subsequently, T2DM (Hampp et al., Use of AntidiabeticDrugs in the U.S., 2003-2012, Diabetes Care 37:1367-1374, 2014). Thesemay be grouped into six major classes, each acting through a differentprimary mechanism.

Insulin secretogogues, including sulphonyl-ureas (e.g., glipizide,glimepiride, glyburide), meglitinides (e.g., nateglidine, repaglinide),dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., sitagliptin,vildagliptin, alogliptin, dutogliptin, linagliptin, saxogliptin), andglucagon-like peptide-1 receptor (GLP-1R) agonists (e.g., liraglutide,albiglutide, exenatide, lixisenatide, dulaglutide, semaglutide), whichenhance secretion of insulin by acting on the pancreatic beta-cells.Sulphonyl-ureas and meglitinides have limited efficacy and tolerability,cause weight gain and often induce hypoglycemia. DPP-IV inhibitors havelimited efficacy. Marketed GLP-1R agonists are peptides administered bysubcutaneous injection. Liraglutide is additionally approved for thetreatment of obesity.

Biguanides (e.g., metformin) are thought to act primarily by decreasinghepatic glucose production. Biguanides often cause gastrointestinaldisturbances and lactic acidosis, further limiting their use.

Inhibitors of alpha-glucosidase (e.g., acarbose) decrease intestinalglucose absorption. These agents often cause gastrointestinaldisturbances.

Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on a specificreceptor (peroxisome proliferator-activated receptor-gamma) in theliver, muscle and fat tissues. They regulate lipid metabolismsubsequently enhancing the response of these tissues to the actions ofinsulin. Frequent use of these drugs may lead to weight gain and mayinduce edema and anemia.

Insulin is used in more severe cases, either alone or in combinationwith the above agents, and frequent use may also lead to weight gain andcarries a risk of hypoglycemia.

Sodium-glucose linked transporter cotransporter 2 (SGLT2) inhibitors(e.g., dapagliflozin, empagliflozin, canagliflozin, ertugliflozin)inhibit reabsorption of glucose in the kidneys and thereby lower glucoselevels in the blood. This emerging class of drugs may be associated withketoacidosis and urinary tract infections.

However, with the exception of GLP-1R agonists and SGLT2 inhibitors, thedrugs have limited efficacy and do not address the most importantproblems, the declining β-cell function and the associated obesity.

Obesity is a chronic disease that is highly prevalent in modem societyand is associated with numerous medical problems including hypertension,hypercholesterolemia, and coronary heart disease. It is further highlycorrelated with T2DM and insulin resistance, the latter of which isgenerally accompanied by hyperinsulinemia or hyperglycemia, or both. Inaddition, T2DM is associated with a two to fourfold increased risk ofcoronary artery disease. Presently, the only treatment that eliminatesobesity with high efficacy is bariatric surgery, but this treatment iscostly and risky. Pharmacological intervention is generally lessefficacious and associated with side effects.

There is therefore a need for more efficacious pharmacologicalintervention with fewer side effects and convenient administration.

Although T2DM is most commonly associated with hyperglycemia and insulinresistance, other diseases associated with T2DM include hepatic insulinresistance, impaired glucose tolerance, diabetic neuropathy, diabeticnephropathy, diabetic retinopathy, obesity, dyslipidemia, hypertension,hyperinsulinemia and nonalcoholic fatty liver disease (NAFLD).

NAFLD is the hepatic manifestation of metabolic syndrome, and is aspectrum of hepatic conditions encompassing steatosis, non-alcoholicsteatohepatitis (NASH), fibrosis, cirrhosis and ultimatelyhepatocellular carcinoma. NAFLD and NASH are considered the primaryfatty liver diseases as they account for the greatest proportion ofindividuals with elevated hepatic lipids. The severity of NAFLD/NASH isbased on the presence of lipid, inflammatory cell infiltrate, hepatocyteballooning, and the degree of fibrosis. Although not all individualswith steatosis progress to NASH, a substantial portion does.

GLP-1 is a 30 amino acid long incretin hormone secreted by the L-cellsin the intestine in response to ingestion of food. GLP-1 has been shownto stimulate insulin secretion in a physiological and glucose-dependentmanner, decrease glucagon secretion, inhibit gastric emptying, decreaseappetite, and stimulate proliferation of beta-cells. In non-clinicalexperiments GLP-1 promotes continued beta-cell competence by stimulatingtranscription of genes important for glucose-dependent insulin secretionand by promoting beta-cell neogenesis (Meier et al., Biodrugs. 17(2):93-102, 2013).

In a healthy individual, GLP-1 plays an important role regulatingpost-prandial blood glucose levels by stimulating glucose-dependentinsulin secretion by the pancreas resulting in increased glucoseabsorption in the periphery. GLP-1 also suppresses glucagon secretion,leading to reduced hepatic glucose output. In addition, GLP-1 delaysgastric emptying and slows small bowel motility delaying foodabsorption. In people with T2DM, the normal post-prandial rise in GLP-1is absent or reduced (Vilsboll et al., Diabetes. 50:609-613, 2001).

Hoist (Physiol. Rev. 87:1409, 2007) and Meier (Nat. Rev. Endocrinol.8:728, 2012) describe that GLP-1 receptor agonists, such as GLP-1,liraglutide and exendin-4, have 3 major pharmacological activities toimprove glycemic control in patients with T2DM by reducing fasting andpostprandial glucose (FPG and PPG): (i) increased glucose-dependentinsulin secretion (improved first- and second-phase), (ii) glucagonsuppressing activity under hyperglycemic conditions, (iii) delay ofgastric emptying rate resulting in retarded absorption of meal-derivedglucose.

There remains a need for an easily-administered prevention and/ortreatment for cardiometabolic and associated diseases.

SUMMARY OF THE INVENTION

In one aspect, the present disclosure provides a compound of any one ofthe formulae described herein (e.g, Structural Formula (I), (I-1),(I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′),(II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer,solvate, or hydrate thereof.

In one aspect, the present disclosure provides a pharmaceuticalcomposition comprising a compound of any one of the formulae describedherein (e.g., Structural Formula (I), (I-1), (I-2), (II), (III), (I-A),(I-B), (I-C), (I-D), (II-A), (II-B), (II-B′), (II-C), or (II-D)), or apharmaceutically acceptable salt, stereoisomer, solvate, or hydratethereof, as defined in any one of the embodiments described herein, in amixture with at least one pharmaceutically acceptable excipient.

In another aspect, the present disclosure provides a compound of any oneof the formulae described herein (e.g., Structural Formula (I), (I-1),(I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′),(II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer,solvate, or hydrate thereof, as defined in any one of the embodimentsdescribed herein, for use as a medicament.

In another aspect, the present disclosure provides a compound of any oneof the formulae described herein (e.g., Structural Formula (I), (I-1),(I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′),(II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer,solvate, or hydrate thereof, as defined in any one of the embodimentsdescribed herein, for use in the prevention and/or treatment ofcardiometabolic and associated diseases discussed herein, includingT2DM, pre-diabetes, NASH, and cardiovascular disease.

In another aspect, the present disclosure provides a method of treatinga disease for which an agonist of GLP-1R is indicated, in a subject inneed of such prevention and/or treatment, comprising administering tothe subject a therapeutically effective amount of a compound of any oneof the formulae described herein (e.g., Structural Formula (I), (I-1),(I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′),(II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer,solvate, or hydrate thereof, as defined in any one of the embodimentsdescribed herein.

In another aspect, the present disclosure provides a use of a compoundof any one of the formulae described herein (e.g., Structural Formula(I), (I-1), (I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A),(II-B), (II-B′), (II-C), or (II-D)), or a pharmaceutically acceptablesalt, stereoisomer, solvate, or hydrate thereof, as defined in any oneof the embodiments described herein, for the manufacture of a medicamentfor treating a disease or condition for which an agonist of the GLP-1Ris indicated.

In another aspect, the present disclosure provides a compound of any oneof the formulae described herein (e.g., Structural Formula (I), (I-1),(I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′),(II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer,solvate, or hydrate thereof, as defined in any one of the embodimentsdescribed herein, for use in the treatment of a disease or condition forwhich an agonist of GLP-1R is indicated.

In another aspect, the present disclosure provides a pharmaceuticalcomposition for the treatment of a disease or condition for which anagonist of the GLP-1R is indicated, comprising a compound of any one ofthe formulae described herein (e.g., Structural Formula (I), (I-1),(I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′),(II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer,solvate, or hydrate thereof, as defined in any one of the embodimentsdescribed herein.

Every Example or pharmaceutically acceptable salt thereof may be claimedindividually or grouped together in any combination with any number ofeach and every embodiment described herein.

The present disclosure also provides a pharmaceutical compositioncomprising a compound of any one of the formulae described herein (e.g.,Structural Formula (I), (I-1), (I-2), (II), (III), (I-A), (I-B), (I-C),(I-D), (II-A), (II-B), (II-B′), (II-C), or (II-D)), or apharmaceutically acceptable salt, stereoisomer, solvate, or hydratethereof, as defined in any one of the embodiments described herein, foruse in the treatment and/or prevention of cardiometabolic and associateddiseases discussed herein, including T2DM, pre-diabetes, NASH, andcardiovascular disease.

In another aspect, the present disclosure provides a compound of any oneof the formulae described herein (e.g., Structural Formula (I), (I-1),(I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-B′),(II-C), or (II-D)), or a pharmaceutically acceptable salt, stereoisomer,solvate, or hydrate thereof, as defined in any one of the embodimentsdescribed herein, for use in the treatment and/or treatment forcardiometabolic and associated diseases including diabetes (T1D and/orT2DM, including pre-diabetes), idiopathic T1D (Type 1b), latentautoimmune diabetes in adults (LADA), early-onset T2DM (EOD),youth-onset atypical diabetes (YOAD), maturity onset diabetes of theyoung (MODY), malnutrition-related diabetes, gestational diabetes,hyperglycemia, insulin resistance, hepatic insulin resistance, impairedglucose tolerance, diabetic neuropathy, diabetic nephropathy, kidneydisease (e.g, acute kidney disorder, tubular dysfunction,proinflammatory changes to the proximal tubules), diabetic retinopathy,adipocyte dysfunction, visceral adipose deposition, sleep apnea, obesity(including hypothalamic obesity and monogenic obesity) and relatedcomorbidities (e.g., osteoarthritis and urine incontinence), eatingdisorders (including binge eating syndrome, bulimia nervosa, andsyndromic obesity such as Prader-Willi and Bardet-Biedl syndromes),weight gain from use of other agents (e.g., from use of steroids andantipsychotics), excessive sugar craving, dyslipidemia (includinghyperlipidemia, hypertriglyceridemia, increased total cholesterol, highLDL cholesterol, and low HDL cholesterol), hyperinsulinemia, NAFLD(including related diseases such as steatosis, NASH, fibrosis,cirrhosis, and hepatocellular carcinoma), cardiovascular disease,atherosclerosis (including coronary artery disease), peripheral vasculardisease, hypertension, endothelial dysfunction, impaired vascularcompliance, congestive heart failure, myocardial infarction (e.g.necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke,traumatic brain injury, pulmonary hypertension, restenosis afterangioplasty, intermittent claudication, post-prandial lipemia, metabolicacidosis, ketosis, arthritis, osteoporosis, Parkinson's Disease, leftventricular hypertrophy, peripheral arterial disease, maculardegeneration, cataract, glomerulosclerosis, chronic renal failure,metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris,thrombosis, atherosclerosis, transient ischemic attacks, vascularrestenosis, impaired glucose metabolism, conditions of impaired fastingplasma glucose, hyperuricemia, gout, erectile dysfunction, skin andconnective tissue disorders, psoriasis, foot ulcerations, ulcerativecolitis, hyper apo B lipoproteinemia, Alzheimer's Disease,schizophrenia, impaired cognition, inflammatory bowel disease, shortbowel syndrome, Crohn's disease, colitis, irritable bowel syndrome,prevention or treatment of Polycystic Ovary Syndrome and treatment ofaddiction (e.g., alcohol and/or drug abuse).

In another aspect, the present disclosure provides a method of enhancingor stimulating GLP-1R-mediated cAMP signaling with reducedβ-arrestin/arrestin-2 recruitment, comprising administering a compoundof any one of the formulae described herein (e.g., Structural Formula(I), (I-1), (I-2), (II), (III), (I-A), (I-B), (I-C), (I-D), (II-A),(II-B), (II-B′), (II-C), or (II-D)), or a pharmaceutically acceptablesalt, stereoisomer, solvate, or hydrate thereof, as defined in any oneof the embodiments described herein. This is partly based on thesurprising finding that the compounds of the present disclosure, whilebeing full agonists of GLP-1R-mediated cAMP signaling, are partialagonists of β-arrestin recruitment to activated GLP-1R, compared to thenatural GLP-1R ligand GLP-1, in that maximal β-arrestin recruitment toactivated GLP-1R by the compounds of the present disclosure is lowerthan maximal β-arrestin recruitment by GLP-1. Such partial and/or biasedagonists of GLP-1R for cAMP signaling may provide a more sustained cAMPsignaling activity for better efficacy and lowered side effects.

Thus, the method of the present disclosure may be advantageously usedfor the treatment of any of the diseases or conditions described herein,such as type II diabetes (T2D) and related diseases.

In certain embodiments, the treatment elicits a glycemic benefit withoutconcomitant increase, or at least reduced increase, in a GI side effectsuch as nausea, vomiting, or diarrhea. In certain embodiments, thetreatment has greater tolerability compared to a control treatment thathas normal or enhanced β-arrestin recruitment (such as β-arrestinrecruitment by GLP-1).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows dose-response curves for the GLP-1R/β-Arrestin recruitmentassay using certain compounds of the present disclosure and GLP-1 (7-37)as control. The vertical axis represents relative effects of the testcompounds normalized to percentage of effect by the natural ligand GLP-1(7-37). FIG. 1 compares Compounds 74-91, 93-95, 100, and 101 to GLP-1(7-37).

FIG. 2 shows dose-response curves for the GLP-1R/β-Arrestininternalization assay using certain compounds of the present disclosureand GLP-1 (7-37) as control. The vertical axis represents relativeeffects of the test compounds normalized to percentage of effect by thenatural ligand GLP-1 (7-37). The two panels in FIG. 2 compare Compounds74-80, 93-95, 100, and 101 (left panel), and Compounds 81-91 (rightpanel), respectively, to GLP-1 (7-37).

FIG. 3 shows NanoBit assay time course responses for both GLP-1 (7-37)and Compound 94 at different compound concentrations.

FIG. 4 shows dose-response curves for the GLP-1R/β-Arrestin NanoBitassay using certain compounds of the present disclosure and GLP-1 (7-37)as control. The vertical axis represents relative effects of the testcompounds normalized to percentage of effect by the natural ligand GLP-1(7-37). The two panels in FIG. 4 compare Compounds 74-91, 93-95, 100,and 101 to GLP-1 (7-37), at 3 min. and 5 min. readouts, respectively.

FIG. 5 shows cAMP assay results using a monkey GLP-1R, for selectedcompounds of the present disclosure (i.e., Compounds 75, 84, 93, and 94)and GLP-1 (7-37) as control.

DETAILED DESCRIPTION OF THE INVENTION 1. Compounds

In a first embodiment, the present disclosure provides a compoundrepresented by structural formula (I):

or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydratethereof, wherein:

indicates a single bond or a double bond;

X¹, X², X³, X⁴, and X⁵ are each independently selected from N and CH;

W is selected from O, S, CR⁵R⁶, and NR^(5′);

ring B is 6-membered heteroaryl, 6-membered monocyclic heterocyclyl, orphenyl, wherein Y¹ is selected from N, NH, CH, and CH₂;

ring C is cyclohexyl, phenyl, or pyridyl;

L is CHR^(d), O, S, or NR^(5′);

ring D is bicyclic heteroaryl;

EE is —COOH or a carboxylic group surrogate, optionally, the carboxylicgroup surrogate is:

each R^(a) and R^(b) are independently selected from hydrogen,deuterium, halogen, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR^(5′)R^(6′),6-10membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated orpartially saturated cycloalkyl and 3-8 membered saturated or partiallysaturated heterocyclyl, wherein the C₁-C₆ alkyl or C₁-C₆ alkoxyrepresented by R^(a)/R^(b) is optionally substituted with one or moregroups selected from halogen, oxo, CN, OH, and C₃-C₆ saturated orpartially saturated cycloalkyl; and wherein the aryl, heteroaryl,saturated or partially saturated cycloalkyl, or saturated or partiallysaturated heterocyclyl represented by R^(a)/R^(b) or in the grouprepresented by R^(a)/R^(b) is optionally substituted with one or moregroups selected from halogen, oxo (as appropriate), CN, OH, C₁—C, alkyl(optionally substituted with 1 to 3 groups selected from F, OH, andOCH₃), and C₁—C, alkoxy (optionally substituted with 1 to 3 groupsselected from F, OH, and OCH₃), and NR^(5′)R^(6′);

each R^(c) and R^(d) are independently selected from hydrogen,deuterium, halogen, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR^(5′)R^(6′),6-10membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated orpartially saturated cycloalkyl and 3-8 membered saturated or partiallysaturated heterocyclyl, wherein the C₁-C₆ alkyl or C₁-C₆ alkoxyrepresented by R^(c)/R^(d) is optionally substituted with one or moregroups selected from halogen, oxo, CN, OH, and C₃-C₆ saturated orpartially saturated cycloalkyl; and wherein the aryl, heteroaryl,saturated or partially saturated cycloalkyl, or saturated or partiallysaturated heterocyclyl represented by R^(c)/R^(d) or in the grouprepresented by R^(c)/R^(d) is optionally substituted with one or moregroups selected from halogen, oxo (as appropriate), CN, andNR^(5′)R^(6′);

each R¹ is independently selected from H, deuterium, halogen, —CN, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl,NR^(5′)R^(6′),6-10 membered aryl, 5-8 membered heteroaryl, 3-8 memberedsaturated or partially saturated cycloalkyl and 3-8 membered saturatedor partially saturated heterocyclyl, wherein the C₁-C₆ alkyl, C₁-C₆alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl represented by R¹ is optionallysubstituted with one or more groups selected from halogen, oxo, CN, CF₃,OH, OCH₃, OCH₂CH₃, and saturated or partially saturated C₃-C₆ cycloalkyl(optionally substituted with one or more groups selected from halogen,oxo, CN, CF₃, OH, OCH₃, OCH₂CH₃); and wherein the aryl, heteroaryl,saturated or partially saturated cycloalkyl, or saturated or partiallysaturated heterocyclyl represented by R¹ or in the group represented byR¹ is optionally substituted with one or more groups selected fromhalogen, oxo (as appropriate), CN, OH, C₁-C₃ alkyl (optionallysubstituted with 1 to 3 groups selected from F, OH, and OCH₃), and C₁-C₃alkoxy (optionally substituted with 1 to 3 groups selected from F, OH,and OCH₃), and NR^(5′)R^(6′).

each R² is independently selected from H, deuterium, halogen, —CN, OH,oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR^(5′)R^(6′),6-10 membered aryl, 5-8membered heteroaryl, 3-8 membered saturated or partially saturatedcycloalkyl and 3-8 membered saturated or partially saturatedheterocyclyl, wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy represented by R²is optionally substituted with one or more groups selected from halogen,oxo, CN, CF₃, OH, OCH₃, OCH₂CH₃, and saturated or partially saturatedC₃-C₆ cycloalkyl (optionally substituted with one or more groupsselected from halogen, oxo, CN, CF₃, OH, OCH₃, OCH₂CH₃); and wherein thearyl, heteroaryl, saturated or partially saturated cycloalkyl, orsaturated or partially saturated heterocyclyl represented by R² or inthe group represented by R² is optionally substituted with one or moregroups selected from halogen, oxo (as appropriate), CN, OH, C₁-C₃ alkyl(optionally substituted with 1 to 3 groups selected from F, OH, andOCH₃), and C₁-C₃ alkoxy (optionally substituted with 1 to 3 groupsselected from F, OH, and OCH₃), and NR^(5′)R^(6′);

each R³ is independently selected from H, deuterium, halogen, —CN, OH,oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR^(5′)R^(6′),6-10 membered aryl, 5-8membered heteroaryl, 3-8 membered saturated or partially saturatedcycloalkyl and 3-8 membered saturated or partially saturatedheterocyclyl, wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy represented by R³is optionally substituted with one or more groups selected from halogen,oxo, CN, CF₃, OH, OCH₃, OCH₂CH₃, and saturated or partially saturatedC₃-C₆ cycloalkyl (optionally substituted with one or more groupsselected from halogen, oxo, CN, CF₃, OH, OCH₃, OCH₂CH₃); and wherein thearyl, heteroaryl, saturated or partially saturated cycloalkyl, orsaturated or partially saturated heterocyclyl represented by R³ or inthe group represented by R³ is optionally substituted with one or moregroups selected from halogen, oxo (as appropriate), CN, OH, C₁-C₃ alkyl(optionally substituted with 1 to 3 groups selected from F, OH, andOCH₃), and C₁-C₃ alkoxy (optionally substituted with 1 to 3 groupsselected from F, OH, and OCH₃), and NR^(5′)R^(6′);

each R⁴ is independently selected from H, deuterium, halogen, OH, —CN,C₁-C₆ alkyl, C₁-C₆ alkoxy, and NR^(5′)R^(6′), wherein the C₁-C₆ alkyland C₁-C₆ alkoxy represented by R⁴ is optionally substituted with one ormore groups selected from halogen, oxo, CN, CF₃, and saturated orpartially saturated C₃-C₆ cycloalkyl (optionally substituted with one ormore groups selected from halogen, oxo, CN, CF₃, OH, OCH₃, OCH₂CH₃);

R⁵ and R⁶ are each independently selected from hydrogen, deuterium,halogen, CN, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR^(5′)R^(6′),6-10 memberedaryl, 5-8 membered heteroaryl, 3-8 membered saturated or partiallysaturated cycloalkyl and 3-8 membered saturated or partially saturatedheterocyclyl, wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy represented by R⁵or R⁶ is optionally substituted with one or more groups selected fromhalogen, oxo, CN, CF₃, OH, OCH₃, OCH₂CH₃, and saturated or partiallysaturated C₃-C₆ cycloalkyl (optionally substituted with one or moregroups selected from halogen, oxo, CN, CF₃, OH, OCH₃, OCH₂CH₃); andwherein the aryl, heteroaryl, saturated or partially saturatedcycloalkyl, or saturated or partially saturated heterocyclyl representedby R⁵ or R⁶ or in the group represented by R⁵ or R⁶ is optionallysubstituted with one or more groups selected from halogen, oxo (asappropriate), CN, OH, C₁-C₃ alkyl (optionally substituted with 1 to 3groups selected from F, OH, and OCH₃), and C₁-C₃ alkoxy (optionallysubstituted with 1 to 3 groups selected from F, OH, and OCH₃), andNR^(5′)R^(6′).

R⁵ and R⁶ are each independently selected from hydrogen and C₁-C₆ alkyl;

wherein optionally two R¹; two R²; two R³; two R⁴; R¹ and R²; R² and R³;R^(a) and R¹; R^(a) and R²; R¹ and any of R⁵, R^(5′) (in the grouprepresented by W), or R⁶; R^(a) and any of R⁵, R^(5′) (in the grouprepresented by W), or R⁶; R² and any of R⁵, R^(5′) (in the grouprepresented by W), or R⁶; R⁵ and R⁶; any of two groups selected fromR^(c), R^(d), R^(e), and R^(f); or R⁴ and any one of R^(c), R^(d),R^(e), and R^(f); taken together with their respective interveningcarbon or hetero atom(s), form phenyl, 5-6 membered heteroaryl, 4-8membered saturated or partially saturated cycloalkyl or 4-8 memberedsaturated or partially saturated heterocyclyl, and each of which isoptionally substituted with one or more groups selected from halogen,—CN, —OH, CF₃, C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂, —NHC₁-C₆ alkyl, —N(C₁-C₆alkyl)₂, oxo, and saturated or partially saturated C₃-C₆ cycloalkyl,wherein the C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted withone or more groups selected from halogen, oxo, CN, CF₃, OH, OCH₃,OCH₂CH₃, and saturated or partially saturated C₃-C₆ cycloalkyl, whereinthe cycloalkyl is optionally substituted with one or more groupsselected from halogen, oxo, CN, CF₃, OH, OCH₃, OCH₂CH₃;

m is an integer selected from 0, 1, 2, 3, and 4;

n is an integer selected from 0, 1, 2, 3, 4, and 5;

o is an integer selected from 0, 1, 2, 3, and 4; and

p is an integer selected from 0, 1, 2, 3, and 4.

In a second embodiment, the present disclosure provides a compoundaccording to the first embodiment, wherein the compound is representedby structural formula (II):

or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydratethereof, wherein:

X¹, X², X³, X⁴, and X⁵ are each independently selected from N and CH;wherein no more than three of X¹, X², X³, X⁴, and X⁵ are N and whereinring A does not contain 3 nitrogen ring atoms at 3 contiguous positions;

ring B is 6 membered heteroaryl or phenyl, wherein Y¹, Y³, Y⁴, and Y⁵are each independently selected from N or CH; wherein there are no morethan 3 nitrogen ring atoms in ring B and ring B does not contain 3nitrogen ring atoms at 3 contiguous positions;

T² is selected from N and C;

T⁴ is selected from N, NR⁴, O, S, and CR⁴;

T⁶, T⁷, and T⁸ are each independently selected from N and CR⁴;

wherein no more than 4 of T², T⁴, T⁶, T⁷, and T⁸ are selected from N, O,and S.

In a third embodiment, the present disclosure provides a compoundaccording to the first or second embodiment, or a pharmaceuticallyacceptable salt, stereoisomer, solvate, or hydrate thereof, wherein

W is O, NH or CH₂;

R^(a) is H, CH₃, or CF₃;

R^(b) is selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,NR^(5′)R^(6′),6-10 membered aryl, 5-6 membered heteroaryl, 3-6 memberedsaturated or partially saturated cycloalkyl and 3-7 membered saturatedor partially saturated heterocyclyl, wherein the C₁-C₆ alkyl or C₁-C₆alkoxy represented by R^(b) is optionally substituted with one or moregroups selected from halogen, oxo, CN, OH, and C₃-C₆ saturated orpartially saturated cycloalkyl; and wherein the aryl, heteroaryl,saturated or partially saturated cycloalkyl, or saturated or partiallysaturated heterocyclyl represented by R^(b) or in the group representedby R^(b) is optionally substituted with one or more groups selected fromhalogen, oxo (when R^(b) is non-aromatic), CN, OH, C₁-C₃ alkyl(optionally substituted with 1 to 3 groups selected from F, OH, andOCH₃), and C₁-C₃ alkoxy (optionally substituted with 1 to 3 groupsselected from F, OH, and OCH₃), and NR^(5′)R^(6′);

R^(c) is selected from hydrogen, halogen, and C₁-C₄ alkyl optionallysubstituted with one or more groups selected from halogen and hydroxy;

R^(d) is H, F, CH₃, or CF₃; and

each R¹ is independently selected from H, deuterium, halogen, —CN, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl,NR^(5′)R^(6′),6-10 membered aryl, 5-8 membered heteroaryl, 3-8 memberedsaturated or partially saturated cycloalkyl and 3-8 membered saturatedor partially saturated heterocyclyl, wherein the C₁-C₆ alkyl, C₁-C₆alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl represented by R¹ is optionallysubstituted with one or more groups selected from halogen, oxo, CN, CF₃,OH, OCH₃, OCH₂CH₃, and saturated or partially saturated C₃-C₆ cycloalkyl(optionally substituted with one or more groups selected from halogen,oxo, CN, CF₃, OH, OCH₃, OCH₂CH₃); and wherein the aryl, heteroaryl,saturated or partially saturated cycloalkyl, or saturated or partiallysaturated heterocyclyl represented by R¹ or in the group represented byR¹ is optionally substituted with one or more groups selected fromhalogen, oxo (when R¹ is non-aromatic), CN, OH, C₁-C₃ alkyl (optionallysubstituted with 1 to 3 groups selected from F, OH, and OCH₃), and C₁-C₃alkoxy (optionally substituted with 1 to 3 groups selected from F, OH,and OCH₃), and NR^(5′)R^(6′).

each R² and R³ are independently selected from H, deuterium, halogen,—CN, OH, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR^(5′)R^(6′), wherein theC₁-C₆ alkyl or C₁-C₆ alkoxy represented by R² and/or R³ is optionallysubstituted with one or more groups selected from halogen, oxo, CN, CF₃,OH, OCH₃, OCH₂CH₃, and saturated or partially saturated C₃-C₆ cycloalkyl(optionally substituted with one or more groups selected from halogen,oxo, CN, CF₃, OH, OCH₃, OCH₂CH₃);

each R⁴ is independently selected from H, deuterium, halogen, OH, —CN,C₁-C₆ alkyl, C₁-C₆ alkoxy, and NR^(5′)R^(6′), wherein the C₁-C₆ alkyland C₁-C₆ alkoxy represented by R⁴ is optionally substituted with one ormore groups selected from halogen, oxo, CN, CF₃, and saturated orpartially saturated C₃-C₆ cycloalkyl (optionally substituted with one ormore groups selected from halogen, oxo, CN, CF₃, OH, OCH₃, OCH₂CH₃); and

o is an integer selected from 0, 1, 2, 3, and 4.

In a fourth embodiment, the present disclosure provides a compoundaccording to the first, second, or third embodiment, wherein thecompound is represented by the structural formula (III):

or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydratethereof, wherein R⁴ is H, F, Cl, methyl, or methoxy.

In a fifth embodiment, the present disclosure provides a compoundaccording to the second, third, or fourth embodiment, or apharmaceutically acceptable salt, stereoisomer, solvate, or hydratethereof, wherein

wherein n is an integer selected from 0, 1, 2, 3, and 4, as appropriate.

In a sixth embodiment, the present disclosure provides a compoundaccording to the first, second, third, fourth, or fifth embodiment, or apharmaceutically acceptable salt, stereoisomer, solvate, or hydratethereof, wherein ring A is

each R¹ is independently selected from halogen, OH, CN, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy,C₁-C₄ hydroxyalkoxy, C₂-C₄ alkenyl, C₂-C₄ alkynyl, —NH₂, —NHC₁-C₄ alkyl,—N(C₁-C₄ alkyl)₂; and m is an integer selected from 0, 1, and 2.

In a seventh embodiment, the present disclosure provides a compoundaccording to the first, second, third, fourth, fifth, or sixthembodiment, or a pharmaceutically acceptable salt, stereoisomer,solvate, or hydrate thereof, wherein EE is COOH.

In an eighth embodiment, the present disclosure provides a compoundaccording to the first, second, third, fourth, fifth, sixth, or seventhembodiment, or a pharmaceutically acceptable salt, stereoisomer,solvate, or hydrate thereof, wherein R^(b) is

each of which is optionally substituted with 1 or 2 groups selected fromhalogen, oxo (when R^(b) is non-aromatic), CN, NR^(5′)R^(6′), C₁-C₄alkyl, and C₁-C₄ alkoxy, wherein the C₁-C₄ alkyl or C₁-C₄ alkoxy in thegroup represented by R^(b) is optionally substituted with 1 or 2 groupsselected from F, OH, and OCH₃.

In a ninth embodiment, the present disclosure provides a compoundaccording to the second, third, fourth, fifth, sixth, seventh, or eighthembodiment, or a pharmaceutically acceptable salt, stereoisomer,solvate, or hydrate thereof, wherein

In a tenth embodiment, the present disclosure provides a compoundaccording to the first, second, third, fourth, fifth, sixth, seventh,eighth, or ninth embodiment, or a pharmaceutically acceptable salt,stereoisomer, solvate, or hydrate thereof, wherein

R³ is halogen, CN, OH, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, orNR^(5′)R^(6′); and

o is an integer selected from 0, 1, 2, 3, and 4.

In an eleventh embodiment, the present disclosure provides a compoundaccording to the first, second, third, fourth, fifth, sixth, seventh,eighth, ninth, or tenth embodiment, or a pharmaceutically acceptablesalt, stereoisomer, solvate, or hydrate thereof, wherein each R² isindependently selected from deuterium, halogen, —CN, OH, C₁-C₂ alkyl,C₁-C₂ haloalkyl, and C₁-C₂ alkoxy; and n is an integer selected from 0,1, 2, 3, and 4.

In a twelfth embodiment, the present disclosure provides a compoundaccording to the first, second, third, fourth, fifth, sixth, seventh,eighth, ninth, tenth, or eleventh embodiment, or a pharmaceuticallyacceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ringA is

each R¹ is independently selected from halogen, OH, CN, C₁-C₂ alkyl,C₁-C₂ haloalkyl, C₁-C₂ hydroxyalkyl, C₁-C₂ alkoxy, C₁-C₂ haloalkoxy,C₁-C₂ hydroxyalkoxy, and C₂-C₄ alkynyl; and m is an integer selectedfrom 0, 1, and 2.

In a thirteenth embodiment, the present disclosure provides a compoundaccording to the fourth, fifth, sixth, seventh, eighth, ninth, tenth,eleventh, or twelfth embodiment, or a pharmaceutically acceptable salt,stereoisomer, solvate, or hydrate thereof, wherein

In a fourteenth embodiment, the present disclosure provides a compoundaccording to the second, third, fourth, fifth, sixth, seventh, eighth,ninth, tenth, eleventh, twelfth, or thirteenth embodiment, or apharmaceutically acceptable salt, stereoisomer, solvate, or hydratethereof, wherein

In a fifteenth embodiment, the present disclosure provides a compoundaccording to the first, second, third, fourth, fifth, sixth, seventh,eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenthembodiment, or a pharmaceutically acceptable salt, stereoisomer,solvate, or hydrate thereof, wherein each R² is independently selectedfrom halogen (e.g., F) or deuterium; and n is an integer selected from0, 1, and 2, provided that when R² is deuterium, ring B is fullysubstituted with deuterium.

In a sixteenth embodiment, the present disclosure provides a compoundaccording to the first, second, third, fourth, fifth, sixth, seventh,eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, orfifteenth embodiment, or a pharmaceutically acceptable salt,stereoisomer, solvate, or hydrate thereof, wherein each R³ is F, Cl orCH₃; and o is 0, 1, or 2.

In a seventeenth embodiment, the present disclosure provides a compoundaccording to the first, second, third, fourth, fifth, sixth, seventh,eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth,fifteenth, or sixteenth embodiment, or a pharmaceutically acceptablesalt, stereoisomer,

-   -   solvate, or hydrate thereof, wherein ring A is

In an eighteenth embodiment, the present disclosure provides a compoundaccording to the first, second, third, fourth, fifth, sixth, seventh,eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth,fifteenth, sixteenth, or seventeenth embodiment, or a pharmaceuticallyacceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ringA is

In a nineteenth embodiment, the present disclosure provides a compoundaccording to the second, third, fourth, fifth, sixth, seventh, eighth,ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth,sixteenth, seventeenth, or eighteenth embodiment, or a pharmaceuticallyacceptable salt, stereoisomer, solvate, or hydrate thereof, wherein

The present disclosure also provides a compound represented bystructural formula (I-1) or (I-2):

or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydratethereof, wherein:

indicates a single bond or a double bond;

X¹, X², X³, X⁴, and X⁵ are each independently selected from N and CH;wherein no more than three of X¹, X², X³, X⁴, and X⁵ are N and whereinring A does not contain 3 nitrogen ring atoms at 3 contiguous positions;

W is selected from O, S, CR⁵R⁶, and NR^(5′);

ring B is 5-6 membered heteroaryl, 5-6 membered monocyclic heterocyclyl,or phenyl;

Z¹ and Z² are each independently selected from N, C, and CH; Z³ and Z⁴are each independently selected from a bond, CH, CH₂, CH═CH, CH₂CH₂,CH₂CH, and CHCH₂; wherein ring C contains no more than two double bonds;

L is CHR^(d), O, S, or NR⁵;

ring D is bicyclic heteroaryl;

EE is —COOH or a carboxylic group surrogate, optionally, the carboxylicgroup surrogate is:

each R^(a) and R^(b) are independently selected from hydrogen,deuterium, halogen, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR^(5′)R^(6′),6-10membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated orpartially saturated cycloalkyl and 3-8 membered saturated or partiallysaturated heterocyclyl, wherein the C₁-C₆ alkyl or C₁-C₆ alkoxyrepresented by R^(a)/R^(b) is optionally substituted with one or moregroups selected from halogen, oxo, CN, OH, and C₃-C₆ saturated orpartially saturated cycloalkyl; and wherein the aryl, heteroaryl,saturated or partially saturated cycloalkyl, or saturated or partiallysaturated heterocyclyl represented by R^(a)/R^(b) or in the grouprepresented by R^(a)/R^(b) is optionally substituted with one or moregroups selected from halogen, oxo (as appropriate), CN, OH, C₁—C, alkyl(optionally substituted with 1 to 3 groups selected from F, OH, andOCH₃), and C₁-C₃ alkoxy (optionally substituted with 1 to 3 groupsselected from F, OH, and OCH₃), and NR^(5′)R^(6′);

each R^(c) and R^(d) are independently selected from hydrogen,deuterium, halogen, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR^(5′)R^(6′),6-10membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated orpartially saturated cycloalkyl and 3-8 membered saturated or partiallysaturated heterocyclyl, wherein the C₁-C₆ alkyl or C₁-C₆ alkoxyrepresented by R^(c)/R^(d) is optionally substituted with one or moregroups selected from halogen, oxo, CN, OH, and C₃-C₆ saturated orpartially saturated cycloalkyl; and wherein the aryl, heteroaryl,saturated or partially saturated cycloalkyl, or saturated or partiallysaturated heterocyclyl represented by R^(c)/R^(d) or in the grouprepresented by R^(c)/R^(d) is optionally substituted with one or moregroups selected from halogen, oxo (as appropriate), CN, andNR^(5′)R^(6′);

each R¹ is independently selected from H, deuterium, halogen, —CN, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl,NR^(5′)R^(6′),6-10 membered aryl, 5-8 membered heteroaryl, 3-8 memberedsaturated or partially saturated cycloalkyl and 3-8 membered saturatedor partially saturated heterocyclyl, wherein the C₁-C₆ alkyl, C₁-C₆alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl represented by R¹ is optionallysubstituted with one or more groups selected from halogen, oxo, CN, CF₃,OH, OCH₃, OCH₂CH₃, and saturated or partially saturated C₃-C₆ cycloalkyl(optionally substituted with one or more groups selected from halogen,oxo, CN, CF₃, OH, OCH₃, OCH₂CH₃); and wherein the aryl, heteroaryl,saturated or partially saturated cycloalkyl, or saturated or partiallysaturated heterocyclyl represented by R¹ or in the group represented byR¹ is optionally substituted with one or more groups selected fromhalogen, oxo (as appropriate), CN, OH, C₁-C₃ alkyl (optionallysubstituted with 1 to 3 groups selected from F, OH, and OCH₃), and C₁-C₃alkoxy (optionally substituted with 1 to 3 groups selected from F, OH,and OCH₃), and NR^(5′)R^(6′).

each R² is independently selected from H, deuterium, halogen, —CN, OH,oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR^(5′)R^(6′),6-10 membered aryl, 5-8membered heteroaryl, 3-8 membered saturated or partially saturatedcycloalkyl and 3-8 membered saturated or partially saturatedheterocyclyl, wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy represented by R²is optionally substituted with one or more groups selected from halogen,oxo, CN, CF₃, OH, OCH₃, OCH₂CH₃, and saturated or partially saturatedC₃-C₆ cycloalkyl (optionally substituted with one or more groupsselected from halogen, oxo, CN, CF₃, OH, OCH₃, OCH₂CH₃); and wherein thearyl, heteroaryl, saturated or partially saturated cycloalkyl, orsaturated or partially saturated heterocyclyl represented by R² or inthe group represented by R² is optionally substituted with one or moregroups selected from halogen, oxo (as appropriate), CN, OH, C₁-C₃ alkyl(optionally substituted with 1 to 3 groups selected from F, OH, andOCH₃), and C₁-C₃ alkoxy (optionally substituted with 1 to 3 groupsselected from F, OH, and OCH₃), and NR^(5′)R^(6′);

each R³ is independently selected from H, deuterium, halogen, —CN, OH,oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR^(5′)R^(6′),6-10 membered aryl, 5-8membered heteroaryl, 3-8 membered saturated or partially saturatedcycloalkyl and 3-8 membered saturated or partially saturatedheterocyclyl, wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy represented by R³is optionally substituted with one or more groups selected from halogen,oxo, CN, CF₃, OH, OCH₃, OCH₂CH₃, and saturated or partially saturatedC₃-C₆ cycloalkyl (optionally substituted with one or more groupsselected from halogen, oxo, CN, CF₃, OH, OCH₃, OCH₂CH₃); and wherein thearyl, heteroaryl, saturated or partially saturated cycloalkyl, orsaturated or partially saturated heterocyclyl represented by R³ or inthe group represented by R³ is optionally substituted with one or moregroups selected from halogen, oxo (as appropriate), CN, OH, C₁-C₃ alkyl(optionally substituted with 1 to 3 groups selected from F, OH, andOCH₃), and C₁-C₃ alkoxy (optionally substituted with 1 to 3 groupsselected from F, OH, and OCH₃), and NR^(5′)R^(6′);

each R⁴ is independently selected from H, deuterium, halogen, OH, —CN,C₁-C₆ alkyl, C₁-C₆ alkoxy, and NR^(5′)R^(6′), wherein the C₁-C₆ alkyland C₁-C₆ alkoxy represented by R⁴ is optionally substituted with one ormore groups selected from halogen, oxo, CN, CF₃, and saturated orpartially saturated C₃-C₆ cycloalkyl (optionally substituted with one ormore groups selected from halogen, oxo, CN, CF₃, OH, OCH₃, OCH₂CH₃);

R⁵ and R⁶ are each independently selected from hydrogen, deuterium,halogen, CN, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR^(5′)R^(6′),6-10 memberedaryl, 5-8 membered heteroaryl, 3-8 membered saturated or partiallysaturated cycloalkyl and 3-8 membered saturated or partially saturatedheterocyclyl, wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy represented by R⁵or R⁶ is optionally substituted with one or more groups selected fromhalogen, oxo, CN, CF₃, OH, OCH₃, OCH₂CH₃, and saturated or partiallysaturated C₃-C₆ cycloalkyl (optionally substituted with one or moregroups selected from halogen, oxo, CN, CF₃, OH, OCH₃, OCH₂CH₃); andwherein the aryl, heteroaryl, saturated or partially saturatedcycloalkyl, or saturated or partially saturated heterocyclyl representedby R⁵ or R⁶ or in the group represented by R⁵ or R⁶ is optionallysubstituted with one or more groups selected from halogen, oxo (asappropriate), CN, OH, C₁-C₃ alkyl (optionally substituted with 1 to 3groups selected from F, OH, and OCH₃), and C₁-C₃ alkoxy (optionallysubstituted with 1 to 3 groups selected from F, OH, and OCH₃), andNR^(5′)R^(6′).

R^(5′) and R^(6′) are each independently selected from hydrogen, andC₁-C₆ alkyl;

wherein optionally two R¹; two R²; two R³; two R⁴; R¹ and R²; R² and R³;R^(a) and R¹; R^(a) and R²; R¹ and any of R⁵, R^(5′) (in the grouprepresented by W), or R⁶; R^(a) and any of R⁵, R^(5′) (in the grouprepresented by W), or R⁶; R² and any of R⁵, R^(5′) (in the grouprepresented by W), or R⁶; R⁵ and R⁶; any of two groups selected fromR^(c), R^(d), R^(e), and R^(f); or R⁴ and any one of R^(c), R^(d),R^(e), and R^(f); taken together with their respective interveningcarbon or hetero atom(s), form phenyl, 5-6 membered heteroaryl, 4-8membered saturated or partially saturated cycloalkyl or 4-8 memberedsaturated or partially saturated heterocyclyl, or the carbon atom of—C(R^(a))—, W, and R², taken together with two adjacent carbon atoms ofring B form

and each of which is optionally substituted with one or more groupsselected from halogen, —CN, —OH, CF₃, C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂,—NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂, oxo, and saturated or partiallysaturated C₃-C₆ cycloalkyl, wherein the C₁-C₆ alkyl and C₁-C₆ alkoxy isoptionally substituted with one or more groups selected from halogen,oxo, CN, CF₃, OH, OCH₃, OCH₂CH₃, and saturated or partially saturatedC₃-C₆ cycloalkyl, wherein the cycloalkyl is optionally substituted withone or more groups selected from halogen, oxo, CN, CF₃, OH, OCH₃,OCH₂CH₃;

m is an integer selected from 0, 1, 2, 3, and 4;

n is an integer selected from 0, 1, 2, 3, 4, and 5;

o is an integer selected from 0, 1, 2, 3, 4, and 5; and

p is an integer selected from 0, 1, 2, 3, and 4.

The present disclosure also provides a compound represented bystructural formula (I-A), (I-B), (I-C), or (I-D):

or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydratethereof, wherein:

indicates a single bond or a double bond;

X¹, X², X³, X⁴, and X⁵ are each independently selected from N and CH;wherein no more than three of X¹, X², X³, X⁴, and X⁵ are N and whereinring A does not contain 3 nitrogen ring atoms at 3 contiguous positions;

W is selected from O, S, CR⁵R⁶, and NR^(5′);

Y¹ is N or CH;

Y³ and Y⁵ are each independently selected from N, CH, O, and S;

Y⁴ is absent, N or CH;

Y^(2′) are each independently N or CH;

Y^(3′) and Y^(5′) are each independently selected from N, CH, O, and S;and

Y^(4′) is absent, N or CH;

wherein there are no more than 3 hetero ring atoms in ring B and whereinring B does not contain 3 hetero ring atoms at 3 contiguous positions;

Z¹ and Z² are each independently selected from N, C, and CH; wherein atleast one of Z¹ and Z² is N; Z³ and Z⁴ are each independently selectedfrom a bond, CH, CH₂, CH═CH, CH₂CH₂, CH₂CH, and CHCH₂; wherein ring Ccontains no more than two double bonds;

T², T³, and T⁴ are each independently selected from N, NR⁴, O, S, C, andCR⁴;

T⁶, T⁷, and T⁸ are each independently selected from N and CR⁴;

wherein no more than 4 of T², T³, T⁴, T⁶, T⁷, and T⁸ are selected fromN, O, and S;

and the remainder of the variables are as defined in the previousembodiments for the compounds represented by structural formula (I-1) or(I-2).

In some embodiments, the present disclosure provides a compoundaccording to structural formula (I-1), (I-2), (I-A), (I-B), (I-C), or(I-D), wherein the compound is represented by structural formula (II-A),(II-B), (II-B′), (II-C) or (II-D):

or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydratethereof, wherein the variables are as defined in the previousembodiments for the compounds represented by structural formula (I-1),(I-2), (I-A), (I-B), (I-C), or (I-D).

In some embodiments, the present disclosure provides a compoundaccording to structural formula (I-1), (I-2), (I-A), (I-B), (I-C),(II-A), (II-B), (II-B′), (II-C), or (II-D) or a pharmaceuticallyacceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ringA is

each R¹ is independently selected from halogen, OH, CN, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy,C₁-C₄ hydroxyalkoxy, C₂-C₄ alkenyl, C₂-C₄ alkynyl, —NH₂, —NHC₁-C₄ alkyl,—N(C₁-C₄ alkyl)₂; and m is an integer selected from 0, 1, and 2; and theremainder of the variables are as defined in the previous embodiments.

In some embodiments, the present disclosure provides a compoundaccording to structural formula (I-1), (I-2), (I-A), (I-B), (I-C),(II-A), (II-B), (II-B′), (II-C), or (II-D), or a pharmaceuticallyacceptable salt, stereoisomer, solvate, or hydrate thereof, wherein ringA is

each R¹ is independently selected from halogen, OH, CN, C₁-C₂ alkyl,C₁-C₂ haloalkyl, C₁-C₂ hydroxyalkyl, C₁-C₂ alkoxy, C₁-C₂ haloalkoxy,C₁-C₂ hydroxyalkoxy, C₂-C₄ alkenyl, C₂-C₄ alkynyl; and m is an integerselected from 0, 1, and 2; and the remainder of the variables are asdefined in the previous embodiments. In a specific embodiment, ring A is

In some embodiments, the present disclosure provides a compoundaccording to structural formula (I-1), (I-2), (I-A), (I-B), (I-C),(II-A), (II-B), (II-B′), (II-C), or (II-D), or a pharmaceuticallyacceptable salt, stereoisomer, solvate, or hydrate thereof, wherein

and the remainder of the variables are as defined in the previousembodiments. In a specific embodiment,

In a more specific embodiment,

In some embodiments, the present disclosure provides a compoundaccording to structural formula (I-1), (I-2), (I-A), (I-B), (I-C),(II-A), (II-B), (II-B′), or (II-C), or a pharmaceutically acceptablesalt, stereoisomer, solvate, or hydrate thereof, wherein

wherein R³ is halogen, CN, OH, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, or NR^(5′)R^(6′); and o is an integer selected from 0, 1, 2, and3; and the remainder of the variables are as defined in the previousembodiments. In a specific embodiment,

wherein R³ is independently halogen, C₁-C₄ alkyl, or C₁-C₄ haloalkyl;and o is 0, 1, or 2. In a more specific embodiment,

In some embodiments, the present disclosure provides a compoundaccording to structural formula (II-A) or (II-B′), or a pharmaceuticallyacceptable salt, stereoisomer, solvate, or hydrate thereof, wherein

and the remainder of the variables are as defined in the previousembodiments. In a specific embodiment, wherein

In a specific embodiment, wherein

In some embodiments, the present disclosure provides a compoundaccording to structural formula (II-D), or a pharmaceutically acceptablesalt, stereoisomer, solvate, or hydrate thereof, wherein

In one embodiment, the compound, or a pharmaceutically acceptable salt,stereoisomer, solvate, or hydrate thereof, is selected from thecompounds disclosed in examples and Table 1.

2. Definitions

The term “halogen,” as used herein, refers to fluoride, chloride,bromide, or iodide.

The term “alkyl” used alone or as part of a larger moiety, such as“alkoxy” or “haloalkyl” and the like, means saturated aliphaticstraight-chain or branched monovalent hydrocarbon radical of formula—C_(n)H_((n+1)). Unless otherwise specified, an alkyl group typicallyhas 1-4 carbon atoms, i.e. (C₁-C₄)alkyl. As used herein, a“(C₁-C₄)alkyl” group means a radical having from 1 to 4 carbon atoms ina linear or branched arrangement. Examples include methyl, ethyl,n-propyl, ios-propyl, and the like.

The term “alkylene” as used herein, means a straight or branched chaindivalent hydrocarbon group of formula —C_(n)H_(2n)—. Non-limitingexamples include ethylene, and propylene.

The term “alkenyl” means an alkyl group in which one or morecarbon/carbon single bond is replaced by a double bond.

The term “alkynyl” means an alkyl group in which one or morecarbon/carbon single bond is replaced by a triple bond.

The term “alkoxy” means an alkyl radical attached through an oxygenlinking atom, represented by —O-alkyl. For example, “(C₁-C₄)alkoxy”includes methoxy, ethoxy, propoxy, and butoxy.

The terms “haloalkyl” and “haloalkoxy” means alkyl or alkoxy, as thecase may be, substituted with one or more halogen atoms.

The terms “hydroxyalkyl” and “hydroxyalkoxy” means alkyl or alkoxy, asthe case may be, substituted with one or more hydroxy groups.

The term “cycloalkyl,” as used herein, means a cyclic, hydrocarbon groupcontaining at least three carbon atoms (e.g., C₃, C₄, C₅, C₆, C₇, C₈, orC₃₋₈ or C₃₋₆). The cycloalkyl may be (fully) saturated or partiallysaturated (i.e., not aromatic), and may contain one or morecarbon-carbon double bond(s).

A fully saturated cycloalkyl has the formula C_(n)H_((2n−1)).Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to12-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, quaternary nitrogen, oxidized nitrogen (e.g, NO), oxygen, andsulfur, including sulfoxide and sulfone (“3-12 membered heterocyclyl”).In some embodiments, a heterocyclyl group is a 3-8 membered non-aromaticring system having ring carbon atoms and 1-4 ring heteroatoms, whereineach heteroatom is independently selected from nitrogen, oxygen, andsulfur (“3-8 membered heterocyclyl”). In heterocyclyl groups thatcontain one or more nitrogen atoms, the point of attachment can be acarbon or nitrogen atom, as valency permits. A heterocyclyl group caneither be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., abicyclic system (“bicyclic heterocyclyl”) or tricyclic system(“tricyclic heterocyclyl”); polycyclic ring systems include fused,bridged, or spiro ring systems). Exemplary monocyclic heterocyclylgroups include azetidinyl, oxetanyl, thietanyl, tetrahydrofiiranyl,pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl,azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, and the like.Heterocyclyl polycyclic ring systems can include heteroatoms in one ormore rings in the polycyclic ring system. Substituents may be present onone or more rings in the polycyclic ring system.

Generally, the cycloalkyl or the heterocyclyl may be unsubstituted, orbe substituted with one or more substituents as valency allows, whereinthe substituents can be independently selected from a number of groupssuch as oxo, —CN, halogen, alkyl and alkoxyl, optionally, the alkylsubstitution may be further substituted.

The term “heteroaryl,” as used herein, refers to a monocyclic ormulticyclic aromatic hydrocarbon in which at least one of the ringcarbon atoms has been replaced with a heteroatom independently selectedfrom oxygen, nitrogen and sulfur. Preferably, the heteroaryl is based ona C₅₋₈ aryl with one or more of its ring carbon atoms replaced by theheteroatom. A heteroaryl group may be attached through a ring carbonatom or, where valency permits, through a ring nitrogen atom. Generally,the heteroaryl may be unsubstituted, or be substituted with one or moresubstituents as valency allows with the substituents being independentlyselected from halogen, OH, alkyl, alkoxyl, and amino (e.g., NH₂,NHalkyl, N(alkyl)₂), optionally, the alkyl may be further substituted.

Certain abbreviations used herein include: Room temperature: RT;Methanol: MeOH; Ethanol: EtOH; Isopropanol: iPrOH; Ethyl acetate: EtOAc;Tetrahydrofuran: THF; Toluene: PhCH₃; Cesium carbonate: Cs₂CO₃; Lithiumbis(trimethylsilyl)amide: LiHMDS; Sodium t-butoxide: NaOtBu; Potassiumt-butoxide: KotBu; Lithium diisopropylamide: LDA; Triethylamine: Et₃N;N,N-diisopropylethyl amine: DIPEA; Potassium carbonate: K₂CO₃; Dimethylformamide: DMF; Dimethyl acetamide: DMAc; Dimethyl sulfoxide: DMSO;N-Methyl-2-pyrrolidinone: NMP; Sodium hydride: NaH; Trifluoroaceticacid: TFA; Trifluoroacetic anhydride: TFAA; Acetic anhydride: Ac₂O;Dichloromethane: DCM; 1,2-Dichloroethane: DCE; Hydrochloric acid: HCl;1,8-Diazabicyclo[5.4.0]undec-7-ene: DBU; Borane-dimethylsulfide complex:BH₃-DMS; Borane-tetrahydrofuran complex: BH₃-THF; Lithium aluminumhydride: LAH; Acetic acid: AcOH; Acetonitrile: MeCN; p-Toluenesulfonicacid: pTSA; Dibenzylidine acetone: DBA;2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene: BINAP;1,1′-Ferrocenediyl-bis(diphenylphosphine): dppf;1,3-Bis(diphenylphosphino)propane: DPPP; 3-Chloroperbenzoic acid:m-CPBA; Tert-Butyl methyl ether: MTBE; Methanesulfonyl: Ms;N-Methylpyrrolidinone: NMP; Thin layer chromatography: TLC;Supercritical fluid chromatography: SFC; 4-(Dimethylamino)pyridine:DMAP; Tert-Butyloxycarbonyl: Boc;1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate: HATU; Petroleum ether: PE;2-(1H-Benzotriazole-1-yl)-1.1.3.3-tetramethyluroniumhexafluorophosphate: HBTU; and2-Amino-2-(hydroxymethyl)propane-1.3-diol: tris;tris(dibenzylideneacetone)dipalladium: Pd₂(dba)₃

¹H Nuclear magnetic resonance (NMR) spectra were in all cases consistentwith the proposed structures. Characteristic chemical shifts (5) aregiven in parts-per-million relative to the residual proton signal in thedeuterated solvent (CHCl₃ at 7.27 ppm; CD₂HOD at 3.31 ppm; MeCN at 1.94ppm; DMSO at 2.50 ppm) and are reported using conventional abbreviationsfor designation of major peaks: e.g. s, singlet; d, doublet; t, triplet;q, quartet; m, multiplet; br, broad. ¹H NMR spectra were obtained withfield strengths of 400 or 600 MHz if not stated.

As used herein, a wavy line denotes a point of attachment of asubstituent to another group.

Pharmaceutically Acceptable Salts

Pharmaceutically acceptable salts of the compounds of any one of theformulae described above include acid addition and base salts.

Suitable acid addition salts are formed from acids which form non-toxicsalts. Examples include the acetate, adipate, aspartate, benzoate,besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate,citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate,gluconate, glucuronate, hexafluorophosphate, hibenzate,hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,isethionate, lactate, malate, maleate, malonate, mesylate,methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate,oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate,tartrate, tosylate, trifluoroacetate, 1,5-naphathalenedisulfonic acidand xinafoate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminium, arginine, benzathine, calcium, choline,diethylamine, bis(2-hydroxyethyl)amine (diolamine), glycine, lysine,magnesium, meglumine, 2-aminoethanol (olamine), potassium, sodium,2-Amino-2-(hydroxymethyl)propane-1,3-diol (tris or tromethamine) andzinc salts.

Hemisalts of acids and bases may also be formed, for example,hemisulfate and hemicalcium salts. For a review on suitable salts, seeHandbook of Pharmaceutical Salts: Properties, Selection, and Use byStahl and Wermuth (Wiley-VCH, 2002). Incorporated herein by reference.

Pharmaceutically acceptable salts of compounds of any one of theformulae described above may be prepared by one or more of threemethods:

(i) by reacting the compound of any one of the formulae described abovewith the desired acid or base;

(ii) by removing an acid- or base-labile protecting group from asuitable precursor of the compound of any one of the formulae describedabove or by ring-opening a suitable cyclic precursor, for example, alactone or lactam, using the desired acid or base; or

(iii) by converting one salt of the compound of any one of the formulaedescribed above to another by reaction with an appropriate acid or baseor by means of a suitable ion exchange column.

All three reactions are typically carried out in solution. The resultingsalt may precipitate out and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionisation in theresulting salt may vary from completely ionised to almost non-ionised.

The compounds of any one of the formulae described above, andpharmaceutically acceptable salts thereof, may exist in unsolvated andsolvated forms.

Solvates and Hydrates

The term “solvate” is used herein to describe a molecular complexcomprising the compound of any one of the formulae described above, or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable solvent molecules, for example, ethanol.

The term “hydrate” is employed when said solvent is water.

A currently accepted classification system for organic hydrates is onethat defines isolated site, channel, or metal-ion coordinatedhydrates—see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed.H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones inwhich the water molecules are isolated from direct contact with eachother by intervening organic molecules. In channel hydrates, the watermolecules lie in lattice channels where they are next to other watermolecules. In metal-ion coordinated hydrates, the water molecules arebonded to the metal ion.

When the solvent or water is tightly bound, the complex may have awell-defined stoichiometry independent of humidity. When, however, thesolvent or water is weakly bound, as in channel solvates and hygroscopiccompounds, the water/solvent content may be dependent on humidity anddrying conditions. In such cases, non-stoichiometry will be the norm.

Stereoisomers and Other Variations

The compounds of any one of the formulae described above may exhibit oneor more kinds of isomerism (e.g. optical, geometric or tautomericisomerism). The compounds of any one of the formulae described above mayalso be isotopically labelled. Such variation is implicit to thecompounds of any one of the formulae described above defined as they areby reference to their structural features and therefore within the scopeof the present disclosure.

Compounds of any one of the formulae described above containing one ormore asymmetric carbon atoms can exist as two or more stereoisomers.Where a compound of any one of the formulae described above contains analkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers arepossible. Where structural isomers are interconvertible via a low energybarrier, tautomeric isomerism (“tautomerism”) can occur. This can takethe form of proton tautomerism in compounds of any one of the formulaedescribed above containing, for example, an imino, keto, or oxime group,or so-called valence tautomerism in compounds which contain an aromaticmoiety. It follows that a single compound may exhibit more than one typeof isomerism.

Compounds having one or more chiral centers can exist in variousstereoisomeric forms. Stereoisomers are compounds that differ only intheir spatial arrangement. Stereoisomers include all diastereomeric,enantiomeric, and epimeric forms as well as racemates and mixturesthereof. The term “geometric isomer” refers to compounds having at leastone double bond, wherein the double bond(s) may exist in cis (alsoreferred to as syn or entgegen (If) or trans (also referred to as antior zusammen (Z)) forms as well as mixtures thereof. When a disclosedcompound is named or depicted by structure without indicatingstereochemistry, it is understood that the name or the structureencompasses one or more of the possible stereoisomers, or geometricisomers, or a mixture of the encompassed stereoisomers or geometricisomers.

When a geometric isomer is depicted by name or structure, it is to beunderstood that the named or depicted isomer exists to a greater degreethan another isomer, that is that the geometric isomeric purity of thenamed or depicted geometric isomer is greater than 50%, such as at least60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Geometric isomericpurity is determined by dividing the weight of the named or depictedgeometric isomer in the mixture by the total weight of all of thegeomeric isomers in the mixture.

Racemic mixture means 50% of one enantiomer and 50% of is correspondingenantiomer. When a compound with one chiral center is named or depictedwithout indicating the stereochemistry of the chiral center, it isunderstood that the name or structure encompasses both possibleenantiomeric forms (e.g., both enantiomerically-pure,enantiomerically-enriched or racemic) of the compound. When a compoundwith two or more chiral centers is named or depicted without indicatingthe stereochemistry of the chiral centers, it is understood that thename or structure encompasses all possible diasteriomeric forms (e.g.,diastereomerically pure, diastereomerically enriched and equimolarmixtures of one or more diastereomers (e.g., racemic mixtures) of thecompound.

Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or stereoisomers by well-known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers anddiastereomers also can be obtained from diastereomerically- orenantiomerically-pure intermediates, reagents, and catalysts bywell-known asymmetric synthetic methods.

When a compound is designated by a name or structure that indicates asingle enantiomer, unless indicated otherwise, the compound is at least60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as“enantiomerically pure”). Optical purity is the weight in the mixture ofthe named or depicted enantiomer divided by the total weight in themixture of both enantiomers.

When the stereochemistry of a disclosed compound is named or depicted bystructure, and the named or depicted structure encompasses more than onestereoisomer (e.g., as in a diastereomeric pair), it is to be understoodthat one of the encompassed stereoisomers or any mixture of theencompassed stereoisomers is included. It is to be further understoodthat the stereoisomeric purity of the named or depicted stereoisomers atleast 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomericpurity in this case is determined by dividing the total weight in themixture of the stereoisomers encompassed by the name or structure by thetotal weight in the mixture of all of the stereoisomers.

The pharmaceutically acceptable salts of compounds of any one of theformulae described above may also contain a counterion which isoptically active (e.g. d-lactate or 1-lysine) or racemic (e.g.dl-tartrate or dl-arginine).

Cis/trans isomers may be separated by conventional techniques well knownto those skilled in the art, for example, chromatography and fractionalcrystallisation.

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC). Alternatively, the racemate (or a racemicprecursor) may be reacted with a suitable optically active compound, forexample, an alcohol, or, in the case where the compound of any one ofthe formulae described above contains an acidic or basic moiety, a baseor acid such as 1-phenylethylamine or tartaric acid. The resultingdiastereomeric mixture may be separated by chromatography and/orfractional crystallization and one or both of the diastereoisomersconverted to the corresponding pure enantiomer(s) by means well known toa skilled person. Chiral compounds of any one of the formulae describedabove (and chiral precursors thereof) may be obtained inenantiomerically-enriched form using chromatography, typically HPLC, onan asymmetric resin with a mobile phase consisting of a hydrocarbon,typically heptane or hexane, containing from 0 to 50% by volume ofisopropanol, typically from 2% to 20%, and from 0 to 5% by volume of analkylamine, typically 0.1% diethylamine. Concentration of the eluateaffords the enriched mixture. Chiral chromatography using sub- andsupercritical fluids may be employed. Methods for chiral chromatographyuseful in some embodiments of the present disclosure are known in theart (see, for example, Smith, Roger M., Loughborough University,Loughborough, UK; Chromatographic Science Series (1998), 75(Supercritical Fluid Chromatography with Packed Columns), pp. 223-249and references cited therein). Columns can be obtained from ChiralTechnologies, Inc, West Chester, Pa., USA, a subsidiary of Daicel®Chemical Industries, Ltd., Tokyo, Japan.

It must be emphasized that the compounds of any one of the formulaedescribed above have been drawn herein in a single tautomeric form, allpossible tautomeric forms are included within the scope of the presentdisclosure.

The present disclosure also includes all pharmaceutically acceptableisotopically-labeled compounds of any one of the formulae describedabove wherein one or more atoms are replaced by atoms having the sameatomic number, but an atomic mass or mass number different from theatomic mass or mass number which predominates in nature.

Examples of isotopes suitable for inclusion in the compounds of thepresent disclosure include isotopes of hydrogen, such as ²H and ³H,carbon, such as ^(n)C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine,such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, andsulfur, such as ³⁵S.

Certain isotopically-labelled compounds of any one of the formulaedescribed above, for example those incorporating a radioactive isotope,are useful in drug and/or substrate tissue distribution studies. Theradioactive isotopes tritium, i.e., ³H, and carbon-14, i.e., ¹⁴C, areparticularly useful for this purpose in view of their ease ofincorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e., ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy.

Isotopically-labeled compounds of any one of the formulae describedabove can generally be prepared by conventional techniques known tothose skilled in the art or by processes analogous to those described inthe accompanying Examples and Preparations using an appropriateisotopically-labeled reagent in place of the non-labeled reagentpreviously employed.

Pharmaceutically acceptable solvates in accordance with the presentdisclosure include those wherein the solvent of crystallization may beisotopically substituted, e.g., D₂O, d₆-acetone, d₆-DMSO.

Prodrugs

One way of carrying out the present disclosure is to administer acompound of any one of the formulae described above in the form of aprodrug. Thus, certain derivatives of a compound of any one of theformulae described above which may have little or no pharmacologicalactivity themselves can, when administered into or onto the body, beconverted into a compound of any one of the formulae described abovehaving the desired activity, for example by hydrolytic cleavage,particularly hydrolytic cleavage promoted by an esterase or peptidaseenzyme. Such derivatives are referred to as “prodrugs.” Furtherinformation on the use of prodrugs may be found in Pro-drugs as NovelDelivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W.Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987(Ed. E. B. Roche, American Pharmaceutical Association). Reference canalso be made to Nature Reviews/Drug Discovery, 7:355, 2008, and CurrentOpinion in Drug Discovery and Development, 10:550, 2007.

Prodrugs in accordance with the present disclosure can, for example, beproduced by replacing appropriate functionalities present in thecompounds of any one of the formulae described above with certainmoieties known to those skilled in the art as “pro-moieties” asdescribed, for example, in Design of Prodrugs by H. Bundgaard (Elsevier,1985) and Y. M. Choi-Sledeski and C. G. Wermuth, Designing Prodrugs andBioprecursors in Practice of Medicinal Chemistry, (Fourth Edition),Chapter 28, 657-696 (Elsevier, 2015).

Thus, a prodrug in accordance with the present disclosure is (a) anester or amide derivative of a carboxylic acid in a compound of any oneof the formulae described above; (b) an ester, carbonate, carbamate,phosphate or ether derivative of a hydroxyl group in a compound of anyone of the formulae described above; (c) an amide, imine, carbamate oramine derivative of an amino group in a compound form any one of theformulae described above; (d) an oxime or imine derivative of a carbonylgroup in a compound of any one of the formulae described above; or (e) amethyl, primary alcohol or aldehyde group that can be metabolicallyoxidized to a carboxylic acid in a compound of any one of the formulaedescribed above.

Some specific examples of prodrugs in accordance with the presentdisclosure include:

(i) where the compound of any one of the formulae described abovecontains a carboxylic acid functionality (—COOH), an ester thereof, suchas a compound wherein the hydrogen of the carboxylic acid functionalityof the compound of any one of the formulae described above is replacedby C₁-C₈ alkyl (e.g. ethyl) or (C₁-C₈ alkyl)C(═O)OCH₂— (e.g.^(t)BuC(═O)OCH₂—);

(ii) where the compound of any one of the formulae described abovecontains an alcohol functionality (—OH), an ester thereof, such as acompound wherein the hydrogen of the alcohol functionality of thecompound of any one of the formulae described above is replaced by—CO(C₁-C₈ alkyl) (e.g. methylcarbonyl) or the alcohol is esterified withan amino acid;

(iii) where the compound of any one of the formulae described abovecontains an alcohol functionality (—OH), an ether thereof, such as acompound wherein the hydrogen of the alcohol functionality of thecompound of any one of the formulae described above is replaced by(C₁-C₈ alkyl)C(═O)OCH₂— or —CH₂OP(═O)(OH)₂;

(iv) where the compound of any one of the formulae described abovecontains an alcohol functionality (—OH), a phosphate thereof, such as acompound wherein the hydrogen of the alcohol functionality of thecompound of any one of the formulae described above is replaced by—P(═O)(OH)₂ or —P(═O)(ONa)₂ or —P(═O)(O⁻)₂Ca²⁺;

(v) where the compound of any one of the formulae described abovecontains a primary or secondary amino functionality (—NH₂ or —NHR whereR≠H), an amide thereof, for example, a compound wherein, as the case maybe, one or both hydrogens of the amino functionality of the compound ofany one of the formulae described above is/are replaced by(C₁-C₁₀)alkanoyl, —COCH₂NH₂ or the amino group is derivatised with anamino acid;

(vi) where the compound of any one of the formulae described abovecontains a primary or secondary amino functionality (—NH₂ or —NHR whereR≠H), an amine thereof, for example, a compound wherein, as the case maybe, one or both hydrogens of the amino functionality of the compound ofany one of the formulae described above is/are replaced by—CH₂OP(═O)(OH)₂;

(vii) where the carboxylic acid group within compound of any one of theformulae described above is replaced by a methyl group, a —CH₂OH groupor an aldehyde group.

Certain compounds of any one of the formulae described above maythemselves act as prodrugs of other compounds of any one of the formulaedescribed above. It is also possible for two compounds of any one of theformulae described above to be joined together in the form of a prodrug.In certain circumstances, a prodrug of a compound of any one of theformulae described above may be created by internally linking twofunctional groups in a compound of any one of the formulae describedabove, for instance by forming a lactone.

References to compounds of any one of the formulae described above aretaken to include the compounds themselves and prodrugs thereof. Thepresent disclosure includes such compounds of any one of the formulaedescribed above as well as pharmaceutically acceptable salts of suchcompounds and pharmaceutically acceptable solvates of said compounds andsalts.

3. Administration and Dosing

Typically, a compound of the present disclosure is administered in anamount effective to treat a condition as described herein. The compoundsof the present disclosure can be administered as compound per se, oralternatively, as a pharmaceutically acceptable salt. For administrationand dosing purposes, the compound per se or pharmaceutically acceptablesalt thereof will simply be referred to as the compounds of the presentdisclosure.

The compounds of the present disclosure are administered by any suitableroute in the form of a pharmaceutical composition adapted to such aroute, and in a dose effective for the treatment intended. The compoundsof the present disclosure may be administered orally, rectally,vaginally, parenterally, or topically.

The compounds of the present disclosure may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, or buccal or sublingual administration may beemployed by which the compound enters the bloodstream directly from themouth.

In another embodiment, the compounds of the present disclosure may alsobe administered directly into the bloodstream, into muscle, or into aninternal organ. Suitable means for parenteral administration includeintravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular and subcutaneous. Suitable devices for parenteraladministration include needle (including microneedle) injectors,needle-free injectors and infusion techniques.

In another embodiment, the compounds of the present disclosure may alsobe administered topically to the skin or mucosa, that is, dermally ortransdermally. In another embodiment, the compounds of the presentdisclosure can also be administered intranasally or by inhalation. Inanother embodiment, the compounds of the present disclosure may beadministered rectally or vaginally. In another embodiment, the compoundsof the present disclosure may also be administered directly to the eyeor ear.

The dosage regimen for the compounds of the present disclosure and/orcompositions containing said compounds is based on a variety of factors,including the type, age, weight, sex and medical condition of thepatient; the severity of the condition; the route of administration; andthe activity of the particular compound employed. Thus the dosageregimen may vary widely. In one embodiment, the total daily dose of acompound of the present disclosure is typically from about 0.001 toabout 100 mg/kg (i.e., mg compound of the present disclosure per kg bodyweight) for the treatment of the indicated conditions discussed herein.In another embodiment, total daily dose of the compound of the presentdisclosure is from about 0.01 to about 30 mg/kg, and in anotherembodiment, from about 0.03 to about 10 mg/kg, and in yet anotherembodiment, from about 0.1 to about 3. It is not uncommon that theadministration of the compounds of the present disclosure will berepeated a plurality of times in a day (typically no greater than 4times). Multiple doses per day typically may be used to increase thetotal daily dose, if desired.

For oral administration, the compositions may be provided in the form oftablets containing 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 30.0 50.0,75.0, 100, 125, 150, 175, 200, 250 and 500 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the patient.A medicament typically contains from about 0.01 mg to about 500 mg ofthe active ingredient, or in another embodiment, from about 1 mg toabout 100 mg of active ingredient. Intravenously, doses may range fromabout 0.01 to about 10 mg/kg/minute during a constant rate infusion.

Suitable subjects according to the present disclosure include mammaliansubjects, including non-human mammal such as primates, rodents (mice,rats, hamsters, rabbits etc). In one embodiment, humans are suitablesubjects. Human subjects may be of either gender and at any stage ofdevelopment.

4. Pharmaceutical Compositions

In another embodiment, the present disclosure comprises pharmaceuticalcompositions. Such pharmaceutical compositions comprise a compound ofthe present disclosure presented with a pharmaceutically acceptablecarrier. Other pharmacologically active substances can also be present.

As used herein, “pharmaceutically acceptable carrier” includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents, and the like that arephysiologically compatible. Examples of pharmaceutically acceptablecarriers include one or more of water, saline, phosphate bufferedsaline, dextrose, glycerol, ethanol and the like, as well ascombinations thereof, and may include isotonic agents, for example,sugars, sodium chloride, or polyalcohols such as mannitol, or sorbitolin the composition. Pharmaceutically acceptable substances such aswetting agents or minor amounts of auxiliary substances such as wettingor emulsifying agents, preservatives or buffers, which enhance the shelflife or effectiveness of the antibody or antibody portion.

The compositions of present disclosure may be in a variety of forms.These include, for example, liquid, semi-solid and solid dosage forms,such as liquid solutions (e.g., injectable and infusible solutions),dispersions or suspensions, tablets, pills, powders, liposomes andsuppositories. The form depends on the intended mode of administrationand therapeutic application.

Typical compositions are in the form of injectable or infusiblesolutions, such as compositions similar to those used for passiveimmunization of humans with antibodies in general. One mode ofadministration is parenteral (e.g. intravenous, subcutaneous,intraperitoneal, intramuscular). In another embodiment, the antibody isadministered by intravenous infusion or injection. In yet anotherembodiment, the antibody is administered by intramuscular orsubcutaneous injection.

Oral administration of a solid dose form may be, for example, presentedin discrete units, such as hard or soft capsules, pills, cachets,lozenges, or tablets, each containing a predetermined amount of at leastone compound of the present disclosure. In another embodiment, the oraladministration may be in a powder or granule form. In anotherembodiment, the oral dose form is sub-lingual, such as, for example, alozenge. In such solid dosage forms, the compounds of any one of theformulae described above are ordinarily combined with one or moreadjuvants. Such capsules or tablets may contain a controlled releaseformulation. In the case of capsules, tablets, and pills, the dosageforms also may comprise buffering agents or may be prepared with entericcoatings.

In another embodiment, oral administration may be in a liquid dose form.Liquid dosage forms for oral administration include, for example,pharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art (e.g.,water). Such compositions also may comprise adjuvants, such as wetting,emulsifying, suspending, flavoring (e.g., sweetening), and/or perfumingagents.

In another embodiment, the present disclosure comprises a parenteraldose form.

“Parenteral administration” includes, for example, subcutaneousinjections, intravenous injections, intraperitoneally, intramuscularinjections, intrasternal injections, and infusion. Injectablepreparations (i.e., sterile injectable aqueous or oleaginoussuspensions) may be formulated according to the known art using suitabledispersing, wetting agents, and/or suspending agents.

In another embodiment, the present disclosure comprises a topical doseform.

“Topical administration” includes, for example, transdermaladministration, such as via transdermal patches or iontophoresisdevices, intraocular administration, or intranasal or inhalationadministration. Compositions for topical administration also include,for example, topical gels, sprays, ointments, and creams. A topicalformulation may include a compound which enhances absorption orpenetration of the active ingredient through the skin or other affectedareas. When the compounds of present disclosure are administered by atransdermal device, administration will be accomplished using a patcheither of the reservoir and porous membrane type or of a solid matrixvariety. Typical formulations for this purpose include gels, hydrogels,lotions, solutions, creams, ointments, dusting powders, dressings,foams, films, skin patches, wafers, implants, sponges, fibres, bandagesand microemulsions. Liposomes may also be used. Typical carriers includealcohol, water, mineral oil, liquid petrolatum, white petrolatum,glycerin, polyethylene glycol and propylene glycol. Penetrationenhancers may be incorporated—see, for example, Finnin and Morgan, J.Pharm. Sci., 88:955-958, 1999.

Formulations suitable for topical administration to the eye include, forexample, eye drops wherein the compound of present disclosure isdissolved or suspended in a suitable carrier. A typical formulationsuitable for ocular or aural administration may be in the form of dropsof a micronized suspension or solution in isotonic, pH-adjusted, sterilesaline. Other formulations suitable for ocular and aural administrationinclude ointments, biodegradable (i.e., absorbable gel sponges,collagen) and non-biodegradable (i.e., silicone) implants, wafers,lenses and particulate or vesicular systems, such as niosomes orliposomes. A polymer such as crossed linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example,hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose,or a heteropolysaccharide polymer, for example, gelan gum, may beincorporated together with a preservative, such as benzalkoniumchloride. Such formulations may also be delivered by iontophoresis.

For intranasal administration or administration by inhalation, thecompounds of the present disclosure are conveniently delivered in theform of a solution or suspension from a pump spray container that issqueezed or pumped by the patient or as an aerosol spray presentationfrom a pressurized container or a nebulizer, with the use of a suitablepropellant. Formulations suitable for intranasal administration aretypically administered in the form of a dry powder (either alone, as amixture, for example, in a dry blend with lactose, or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler or as an aerosol sprayfrom a pressurized container, pump, spray, atomizer (preferably anatomizer using electrohydrodynamics to produce a fine mist), ornebulizer, with or without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. Forintranasal use, the powder may comprise a bioadhesive agent, forexample, chitosan or cyclodextrin.

In another embodiment, the present disclosure comprises a rectal doseform. Such rectal dose form may be in the form of, for example, asuppository. Cocoa butter is a traditional suppository base, but variousalternatives may be used as appropriate.

Other carrier materials and modes of administration known in thepharmaceutical art may also be used. Pharmaceutical compositions of thepresent disclosure may be prepared by any of the well-known techniquesof pharmacy, such as effective formulation and administrationprocedures.

The above considerations in regard to effective formulations andadministration procedures are well known in the art and are described instandard textbooks. Formulation of drugs is discussed in, for example,Hoover, John E., Remington's Pharmaceutical Sciences, Mack PublishingCo., Easton, Pa., 1975; Liberman et al., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., Eds.,Handbook of Pharmaceutical Excipients (3^(rd) Ed.), AmericanPharmaceutical Association, Washington, 1999.

5. Co-Administration

The compounds of the present disclosure can be used alone, or incombination with other therapeutic agents. The present disclosureprovides any of the uses, methods or compositions as defined hereinwherein the compound of any embodiment of any one of the formulaedescribed above herein, or pharmaceutically acceptable salt thereof, orpharmaceutically acceptable solvate of said compound or salt, is used incombination with one or more other therapeutic agent discussed herein.

The administration of two or more compounds “in combination” means thatall of the compounds are administered closely enough in time that eachmay generate a biological effect in the same time frame. The presence ofone agent may alter the biological effects of the other compound(s). Thetwo or more compounds may be administered simultaneously, concurrentlyor sequentially. Additionally, simultaneous administration may becarried out by mixing the compounds prior to administration or byadministering the compounds at the same point in time but as separatedosage forms at the same or different site of administration.

The phrases “concurrent administration,” “co-administration,”“simultaneous administration,” and “administered simultaneously” meanthat the compounds are administered in combination.

In another embodiment, the present disclosure provides methods oftreatment that include administering compounds of the present disclosurein combination with one or more other pharmaceutical agents, wherein theone or more other pharmaceutical agents may be selected from the agentsdiscussed herein.

In one embodiment, the compounds of present disclosure are administeredwith an anti-diabetic agent including but not limited to a biguanide(e.g., metformin), a sulfonylurea (e.g., tolbutamide, glibenclamide,gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide,glimepiride, or glipizide), a thiazolidinedione (e.g., pioglitazone,rosiglitazone, or lobeglitazone), a glitazar (e.g., saroglitazar,aleglitazar, muraglitazar or tesaglitazar), a meglitinide (e.g.,nateglinide, repaglinide), a dipeptidyl peptidase 4 (DPP-4) inhibitor(e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin,anagliptin, teneligliptin, alogliptin, trelagliptin, dutogliptin, oromarigliptin), a glitazone (e.g., pioglitazone, rosiglitazone,balaglitazone, rivoglitazone, or lobeglitazone), a sodium-glucose linkedtransporter 2 (SGLT2) inhibitor (e.g., empagliflozin, canagliflozin,dapagliflozin, ipragliflozin, Ipragliflozin, tofogliflozin, sergliflozinetabonate, remogliflozin etabonate, or ertugliflozin), an SGLTL1inhibitor, a GPR40 agonist (FFAR1/FFA1 agonist, e.g. fasiglifam),glucose-dependent insulinotropic peptide (GIP) and analogues thereof, analpha glucosidase inhibitor (e.g. voglibose, acarbose, or miglitol), oran insulin or an insulin analogue, including the pharmaceuticallyacceptable salts of the specifically named agents and thepharmaceutically acceptable solvates of said agents and salts.

In another embodiment, the compounds of present disclosure areadministered with an anti-obesity agent including but not limited topeptide YY or an analogue thereof, a neuropeptide Y receptor type 2(NPYR2) agonist, a NPYR1 or NPYR5 antagonist, a cannabinoid receptortype 1 (CB1R) antagonist, a lipase inhibitor (e.g., orlistat), a humanproislet peptide (HIP), a melanocortin receptor 4 agonist (e.g.,setmelanotide), a melanin concentrating hormone receptor 1 antagonist, afamesoid X receptor (FXR) agonist (e.g. obeticholic acid), zonisamide,phentermine (alone or in combination with topiramate),anorepinephrine/dopamine reuptake inhibitor (e.g., buproprion), anopioid receptor antagonist (e.g., naltrexone), a combination ofnorepinephrine/dopamine reuptake inhibitor and opioid receptorantagonist (e.g., a combination of bupropion and naltrexone), a GDF-15analog, sibutramine, a cholecystokinin agonist, amylin and analoguestherof (e.g., pramlintide), leptin and analogues thereof (e.g.,metroleptin), a serotonergic agent (e.g., lorcaserin), a methionineaminopeptidase 2 (MetAP2) inhibitor (e.g., beloranib or ZGN-1061),phendimetrazine, diethylpropion, benzphetamine, an SGLT2 inhibitor(e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin,Ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozinetabonate, or ertugliflozin), an SGLTL1 inhibitor, a dual SGLT2/SGLT1inhibitor, a fibroblast growth factor receptor (FGFR) modulator, anAMP-activated protein kinase (AMPK) activator, biotin, a MAS receptormodulator, or a glucagon receptor agonist (alone or in combination withanother GLP-1R agonist, e.g., liraglutide, exenatide, dulaglutide,albiglutide, lixisenatide, or semaglutide), including thepharmaceutically acceptable salts of the specifically named agents andthe pharmaceutically acceptable solvates of said agents and salts.

In another embodiment, the compounds of present disclosure areadministered with an agent to treat NASH including but not limited toPF-05221304, an FXR agonist (e.g., obeticholic acid), a PPAR a/5 agonist(e.g, elafibranor), a synthetic fatty acid-bile acid conjugate (e.g.,aramchol), a caspase inhibitor (e.g., emricasan), an anti-lysyl oxidasehomologue 2 (LOXL2) monoclonal antibody (e.g., simtuzumab), a galectin 3inhibitor (e.g., GR-MD-02), a MAPK5 inhibitor (e.g., GS-4997), a dualantagonist of chemokine receptor 2 (CCR2) and CCR5 (e.g., cenicriviroc),a fibroblast growth factor 21 (FGF21) agonist (e.g., BMS-986036), aleukotriene D4 (LTD4) receptor antagonist (e.g., tipelukast), a niacinanalogue (e.g., ARI 3037MO), an ASBT inhibitor (e.g., volixibat), anacetyl-CoA carboxylase (ACC) inhibitor (e.g., NDI 010976), aketohexokinase (KHK) inhibitor, a diacylglyceryl acyltransferase 2(DGAT2) inhibitor, a CB1 receptor antagonist, an anti-CBIR antibody, oran apoptosis signal-regulating kinase 1 (ASK1) inhibitor, including thepharmaceutically acceptable salts of the specifically named agents andthe pharmaceutically acceptable solvates of said agents and salts.

These agents and compounds of the present disclosure can be combinedwith pharmaceutically acceptable vehicles such as saline, Ringer'ssolution, dextrose solution, and the like. The particular dosageregimen, i.e., dose, timing and repetition, will depend on theparticular individual and that individual's medical history.

Acceptable carriers, excipients, or stabilizers are nontoxic torecipients at the dosages and concentrations employed, and may comprisebuffers such as phosphate, citrate, and other organic acids; salts suchas sodium chloride; antioxidants including ascorbic acid and methionine;preservatives (such as octadecyldimethylbenzyl ammonium chloride;hexamethonium chloride; benzalkonium chloride, benzethonium chloride;phenol, butyl or benzyl alcohol; alkyl parabens, such as methyl orpropyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; andm-cresol); low molecular weight (less than about 10 residues)polypeptides; proteins, such as serum albumin, gelatin, or Igs;hydrophilic polymers such as polyvinylpyrrolidone; amino acids such asglycine, glutamine, asparagine, histidine, arginine, or lysine;monosaccharides, disaccharides, and other carbohydrates includingglucose, mannose, or dextrins; chelating agents such as EDTA; sugarssuch as sucrose, mannitol, trehalose or sorbitol; salt-formingcounter-ions such as sodium; metal complexes (e.g., Zn-proteincomplexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ orpolyethylene glycol (PEG). Liposomes containing these agents and/orcompounds of the present disclosure are prepared by methods known in theart, such as described in U.S. Pat. Nos. 4,485,045 and 4,544,545.Liposomes with enhanced circulation time are disclosed in U.S. Pat. No.5,013,556. Particularly useful liposomes can be generated by the reversephase evaporation method with a lipid composition comprisingphosphatidylcholine, cholesterol and PEG-derivatizedphosphatidylethanolamine (PEG-PE). Liposomes are extruded throughfilters of defined pore size to yield liposomes with the desireddiameter.

These agents and/or the compounds of the present disclosure may also beentrapped in microcapsules prepared, for example, by coacervationtechniques or by interfacial polymerization, for example,hydroxymethylcellulose or gelatin-microcapsules andpoly-(methylmethacrylate) microcapsules, respectively, in colloidal drugdelivery systems (for example, liposomes, albumin microspheres,microemulsions, nano-particles and nanocapsules) or in macroemulsions.Such techniques are disclosed in Remington, The Science and Practice ofPharmacy, 20^(th) Ed., Mack Publishing (2000).

Sustained-release preparations may be used. Suitable examples ofsustained-release preparations include semi-permeable matrices of solidhydrophobic polymers containing the compound of any one of the formulaedescribed above, which matrices are in the form of shaped articles,e.g., films, or microcapsules. Examples of sustained-release matricesinclude polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or ‘poly(vinylalcohol)), polylactides (U.S. Pat.No. 3,773,919), copolymers of L-glutamic acid and 7 ethyl-L-glutamate,non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolicacid copolymers such as those used in LUPRON DEPOT™ (injectablemicrospheres composed of lactic acid-glycolic acid copolymer andleuprolide acetate), sucrose acetate isobutyrate, andpoly-D-(−)-3-hydroxybutyric acid.

The formulations to be used for intravenous administration must besterile. This is readily accomplished by, for example, filtrationthrough sterile filtration membranes. Compounds of the presentdisclosure are generally placed into a container having a sterile accessport, for example, an intravenous solution bag or vial having a stopperpierceable by a hypodermic injection needle.

Suitable emulsions may be prepared using commercially available fatemulsions, such as Intralipid™, Liposyn™, Infonutrol™, Lipofundin™ andLipiphysan™. The active ingredient may be either dissolved in apre-mixed emulsion composition or alternatively it may be dissolved inan oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil,corn oil or almond oil) and an emulsion formed upon mixing with aphospholipid (e.g., egg phospholipids, soybean phospholipids or soybeanlecithin) and water. It will be appreciated that other ingredients maybe added, for example glycerol or glucose, to adjust the tonicity of theemulsion. Suitable emulsions will typically contain up to 20% oil, forexample, between 5 and 20%. The fat emulsion can comprise fat dropletsbetween 0.1 and 1.0 μm, particularly 0.1 and 0.5 μm, and have a pH inthe range of 5.5 to 8.0.

The emulsion compositions can be those prepared by mixing a compound ofthe present disclosure with Intralipid™ or the components thereof(soybean oil, egg phospholipids, glycerol and water).

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as set outabove. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in preferably sterile pharmaceutically acceptable solventsmay be nebulised by use of gases. Nebulised solutions may be breatheddirectly from the nebulising device or the nebulising device may beattached to a face mask, tent or intermittent positive pressurebreathing machine. Solution, suspension or powder compositions may beadministered, preferably orally or nasally, from devices which deliverthe formulation in an appropriate manner.

6. Kits

Another aspect of the present disclosure provides kits comprising thecompound of any one of the formulae described above or pharmaceuticalcompositions comprising the compound of any one of the formulaedescribed above of the present disclosure. A kit may include, inaddition to the compound of any one of the formulae described above, ofthe present disclosure or pharmaceutical composition thereof, diagnosticor therapeutic agents. A kit may also include instructions for use in adiagnostic or therapeutic method. In some embodiments, the kit includesthe compound of any one of the formulae described above, or apharmaceutical composition thereof and a diagnostic agent. In otherembodiments, the kit includes the compound of any one of the formulaedescribed above, or a pharmaceutical composition thereof.

In yet another embodiment, the present disclosure comprises kits thatare suitable for use in performing the methods of treatment describedherein. In one embodiment, the kit contains a first dosage formcomprising one or more of the compounds of the present disclosure inquantities sufficient to carry out the methods of the presentdisclosure. In another embodiment, the kit comprises one or morecompounds of the present disclosure in quantities sufficient to carryout the methods of the present disclosure and a container for the dosageand a container for the dosage.

7. Preparation

The compounds of any one of the formulae described above, may beprepared by the general and specific methods described below, using thecommon general knowledge of one skilled in the art of synthetic organicchemistry. Such common general knowledge can be found in standardreference books such as Comprehensive Organic Chemistry, Ed. Barton andOllis, Elsevier; Comprehensive Organic Transformations: A Guide toFunctional Group Preparations, Larock, John Wiley and Sons; andCompendium of Organic Synthetic Methods, Vol. I-XII (published byWiley-Interscience). The starting materials used herein are commerciallyavailable or may be prepared by routine methods known in the art.

In the preparation of the compounds of any one of the formulae describedabove, it is noted that some of the preparation methods described hereinmay require protection of remote functionality (e.g., primary amine,secondary amine, carboxyl in any one of the formulae described aboveprecursors). The need for such protection will vary depending on thenature of the remote functionality and the conditions of the preparationmethods. The need for such protection is readily determined by oneskilled in the art. The use of such protection/deprotection methods isalso within the skill in the art. For a general description ofprotecting groups and their use, see Greene, Protective Groups inOrganic Synthesis, John Wiley & Sons, New York, 1991.

For example, certain compounds contain primary amines or carboxylic acidfunctionalities which may interfere with reactions at other sites of themolecule if left unprotected. Accordingly, such functionalities may beprotected by an appropriate protecting group which may be removed in asubsequent step. Suitable protecting groups for amine and carboxylicacid protection include those protecting groups commonly used in peptidesynthesis (such as N-t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz),and 9-fluorenylmethylenoxycarbonyl (Fmoc) for amines, and lower alkyl orbenzyl esters for carboxylic acids) which are generally not chemicallyreactive under the reaction conditions described and can typically beremoved without chemically altering other functionality in the any oneof the formulae described above compounds.

The Schemes described below are intended to provide a generaldescription of the methodology employed in the preparation of thecompounds of the present disclosure. Some of the compounds of thepresent present disclosure may contain single or multiple chiral centerswith the stereochemical designation (R) or (S). It will be apparent toone skilled in the art that all of the synthetic transformations can beconducted in a similar manner whether the materials are enantioenrichedor racemic. Moreover, the resolution to the desired optically activematerial may take place at any desired point in the sequence using wellknown methods such as described herein and in the chemistry literature.

Amine compounds prepared via methods described herein can be alkylatedwith a protected 2-bromoacetate in the presence of a suitable base suchas K₂CO₃. Et₃N, NaH or LiHMDS in a polar aprotic solvent such as but notlimited to DMF, DMAc, DMSO or NMP to deliver compounds. Standard esterhydrolysis can be performed to provide acids. If Pg² is t-butyl,standard acidic deprotection methods such as TFA/DCM, HCl/1,4-dioxane,HCl/EtOAc or other suitable conditions may be used to deliver acids.

EXAMPFES

Activation of a G protein-coupled receptor (GPCR) GFP-1R by its naturalligand GFP-1 causes recruitment of multiple intracellular proteins, eachof which can activate distinct signaling pathways, most prominently theactivation of downstream G proteins (which can be measured by cAMPproduction), the recruitment of β-Arrestin, and/or the subsequentinternalization of the GPCR (i.e., GFP-1R)-β-Arrestin complex. Unlikethe natural ligand GFP-1, certain GFP-1R agonists are so-called “biasedagonists,” in that they preferentially stimulate subsets among thenatural signaling pathways, such as the G protein activation/cAMPproduction pathway, as compared to the recruitment of β-Arrestin, and/orthe subsequent internalization of the GPCR (i.e., GFP-1R)-β-Arrestincomplex. The assays below provide means to measure the variousdownstream signaling pathways upon activation by the subject compounds.

Biological Example 1: GLP-1R/β-Arrestin Assay and Internalization Assayfor Demonstrating Small Molecule Compound-Mediated GLP-1R/β-ArrestinInteraction Activation

GFP1 plays an important physiological role in maintaining blood glucosehomeostasis. GFP-1R is known to be expressed in pancreatic beta cells.GFP-1 mediates its effects via a Gas-coupled pathway. Activated GFP-1Rstimulates the adenylyl cyclase pathway thus increases the intracellularconcentration of cAMP, which results in increased insulin synthesis andrelease of insulin. Consequently GFP-1R has been suggested as apotential target for the treatment of diabetes.

GLP-1R activation following agonist/ligand binding also leads toβ-arrestin recruitment to the GLP-1 receptor, which blocks GLP-1Rsignaling by, for example, occluding the binding site on GLP-1R forheterotrimeric G-protein to prevent its activation (desensitization),and by linking the GLP-1R to elements of the internalization machinery,such as clathrin and clathrin adaptor AP2, which promotes receptorinternalization via coated pits and subsequent transport to internalcompartments endosomes. Subsequently, the receptor could be eitherdirected to degradation compartments (lysosomes) or recycled back to theplasma membrane where it can again signal. The strength ofarrestin-receptor interaction is believed to play a role in this choice:tighter complexes tend to increase the probability of receptordegradation (Class B), whereas more transient complexes favor recycling(Class A), although this “rule” is far from being absolute.

GLP-1R agonist activity with respect to β-arrestin recruitment can bedetermined with a cell-based functional assay using PathHunter eXpressGLP1R CHO-K1 β-Arrestin GPCR Assay kit (DiscoverX Cat #93-0300E2CP0M).

The PathHunter β-Arrestin GPCR assay technology utilizes aβ-galactosidase (β-gal) enzyme that is split into two fragments, thesmaller Enzyme Donor (ED) and the larger Enzyme Acceptor (EA). Thesefragments can be fused to two proteins that may interact with eachother, such as EA-β-Arrestin and ED-GLP-1R. The fusions can be stablyexpressed in a test cell line, such as the PathHunter CHO-K1 GLP1Rβ-Arrestin cells described below.

Independently, these fragment fusions have no β-gal activity; however,in solution or in a living cell, they can be brought together andcomplement to form an active β-gal enzyme due to the interaction betweenthe fused proteins, thus generating a chemiluminescent signal in thepresence of a suitable β-gal substrate.

In this experiment, PathHunter CHO-K1 GLP1R β-Arrestin cells from theassay kit were plated at a density of 1000 or 2000 cells/20 μl/well in a384-well white/clear bottom plates (Greiner Cat #781098). Frozen cellswere quickly thawed and 10 mL of cell plating medium (provided by thekit) was added to thawed cells. Cells were stored in a 37° C. incubatorunder 5% CO₂ and kept for approximately 48 hours until ready to run theassay.

Reference and test compounds were dissolved in 100% DMSO.5/concentration of an agonist was prepared in serum free DMEM (ThermoCat #11965). 5 μL of this solution was added to 20 μL cell medium inassay plate for a final top concentration of 10 μM. Plates were thenincubated at 37° C. under 5% CO₂ for 90 min.

Following 90 min incubation, detection reagents were made up bycombining 1 part Galacton Star Substrate with 5 parts Emerald II™Solution, and 19 parts of PathHunter Cell Assay Buffer, respectively.12.5 μl detection reagent was added to each well. The plates were thenincubated at room temperature in dark for 60 min. Plates were then readon Envision for 0.1 sec/well. EC₅₀ determinations were made from agonistdose-response curves analyzed with a curve fitting program using a4-parameter logistic dose response equation.

The effect of a small molecule compound, such as one of the instantpresent disclosure, on the GLP-1R/β-Arrestin interaction activation, orβ-Arrestin recruitment, can be demonstrated and measured using the assayand commercial reagents described herein below.

Preparations

Reagents and Consumables:

Reagent Vendor Catalog No. PathHunter eXpress GLP1R Discover X93-0300E2CP0M CHO-K1 β-Arrestin GPCR Assay kit 384 well white/clearbottom Greiner 781098 platesInstruments:

Instrument Vendor Internal Code En Vision PerkinElmer HD-4HYSG2330Media and Solutions

Prepare detection Working Solution by combining 1 part Galacton Star®Substrate with 5 parts Emerald II™ Solution, and 19 parts of PathHunterCell Assay Buffer, respectively.

Once prepared, the working solution is stable for at least 24 hours atroom temperature with no impact on assay performance. Sufficientreagents are provided in each kit to perform the indicated number ofassays.

Procedures

1. Plating Cells

Cells were plated at a density of 1000 or 2000 cells/20 μL/well. Frozencells were quickly thawed and added to 10 mL of cell plating medium.Cells were stored in a 37 degree incubator under 5% CO₂ and left forapproximately 48 hours until ready to run the assay

2. Compound Preparation

-   -   1) Reference agonist compound GLP1 (7-37): dissolved with DMSO        to make 1 mM stock solutions, aliquoted and stored at −80° C.    -   2) Test compounds (such as the compounds of the present        disclosure) came solubilized in 100% DMSO. Prepare 10×        concentration of an agonist in serum free DMEM, and add all        solutions into the compound plate. 2.5 μL of this solution was        added to 20 μL cell medium in assay plate for a final top        concentration of 10 μM. Plates were incubated at 37° C. under 5%        CO₂ for 30 min. An additional 2.5 μL of Buffer was added to the        entire plate for agonist mode and incubated at 37° C. for        another 90 min.        3. Detection Reagents

Following 90 min incubation, detection reagents were made up asdescribed. 12.5 μL was added to all wells. The plates were thenincubated at room temperature in dark for 60 min. Plates were then readon Envision for 0.1 sec/well.

4. β-Arrestin Assay Data Processing

Data analysis: GraphPad Prism 6 was used for establishment ofprogression curve. EC₅₀s or IC50s were determined by 4-parameterlogistic dose response equation.

The β-Arrestin recruitment dose-response curves for selected compoundsof the present disclosure, as compared to GLP-1 (7-37) as a control,were shown in FIG. 1 . The tested compounds include Compounds 74-91,93-95, 100, 101, 257, 262, 263, 266, 267, 271, 276-278, 281, 284, 285,289-293, 303, 305, 307, 308, 310-312, 323, and 331-334. Note that thepartial maximum relative effect B_(max) (at the highest concentrationtested in the assays) for the tested compound generally approaches about20-40% of the B_(max) for the natural ligand GLP-1 (7-37).

β-Arrestin Recruitment As Measured by PathHunter CHO-K1-based Assay

β-arrestin β-arrestin Compound recruitment Compound recruitment No.B_(max) (%) No. B_(max) (%)  74 32.1 (n = 1) 257 31.4 (n = 1)  75 30.4 ±1.15 (n = 2) 262 47.3 ± 4.55 (n = 3)  76 25.1 (n = 1) 263 18.9 (n = 1) 77 39.4 (n = 1) 266 26.7 ± 4.76 (n = 2)  78 22.7 (n = 1) 267 41.7 ±3.45 (n = 3)  79 19.7 (n = 1) 271 28.5 (n = 1)  80 31.6 (n = 1) 276 35.6± 3.90 (n = 2)  81 37.2 (n = 1) 277 39.3 ± 4.96 (n = 3)  82 20.1 (n = 1)278 36.2 ± 5.56 (n = 2)  83 44.6 (n = 1) 281 48.5 ± 6.64 (n = 2)  8433.5 (n = 1) 284 25.5 (n = 1)  85 37.0 (n = 1) 285 24.0 (n = 1)  86 33.5(n = 1) 289 29.6 (n = 1)  87 33.1 (n = 1) 290 39.9 ± 4.40 (n = 2)  8844.6 (n = 1) 291 29.4 ± 6.84 (n = 2)  89 25.3 (n = 1) 292 42.2 ± 2.68 (n= 2)  90 29.5 ± 3.21 (n = 2) 293 32.0 (n = 1)  91 35.8 (n = 1) 303 39.2± 4.75 (n = 2)  93 41.7 (n = 1) 305 31.8 (n = 1)  94 33.3 (n = 1) 30746.8 ± 7.21 (n = 3)  95 29.0 (n = 1) 308 62.8 ± 4.09 (n = 3) 100 0.971(n = 1) 310 37.8 (n = 1) 101 1.05 (n = 1) 311 38.8 ± 7.09 (n = 3) 10228.3 (n = 1) 312 33.4 ± 2.13 (n = 2) — — 323 19.4 (n = 1) — — 331 17.9(n = 1) — — 332 14.5 (n = 1) — — 333 9.75 (n = 1) — — 334 26.6 (n = 1)

Note that in these tested compounds of the present disclosure, with fewexceptions, the partial maximum relative effect B_(max) (at the highestconcentration tested in the assays) for the tested compounds generallyfall within about 10% to about 40% of the B_(max) for the natural ligandGLP-1 (7-37). See B_(max) values in the table above.

A similar assay can also be used to assess the extent of signalattenuation due to GLP-1R internalization (the Internalization Assay).In this assay, activated GLP1R Internalization cells were engineered toco-express an untagged GLP1R, Enzyme Acceptor (EA) tagged β-Arrestin,and a ProLink™ (PK) tag localized to the endosomes. Activation of theGLP1R induces β-Arrestin recruitment, which leads to internalization ofthe Receptor/Arrestin-EA complex in PK-tagged endosomes. This forcescomplementation of the two β-galactosidase enzyme fragments (EA and PK)to form a functional enzyme that hydrolyzes substrate to generate achemiluminescent signal. These cells have been modified to prevent longterm propagation and expansion using a proprietary compound that has noapparent effect on assay performance.

Specifically, PathHunter engineered U2OS cells from the assay kit (Cat#93-0724E3CP0L) were plated at a density of 2000 cells/20 μL/well in a384-well white/clear bottom plates (Greiner Cat #781098). Frozen cellswere quickly thawed and 10 mL of cell plating medium (provided by thekit) was added to thawed cells. Cells were stored in a 37° C. incubatorand kept for approximately 48 hours until ready for the assay.

Reference and test compounds were dissolved in 100% DMSO.5×concentration of an agonist was prepared in serum free DMEM (ThermoCat #11965). 5 μL of this solution was added to 20 μL cell medium inassay plate for a final top concentration of 10 μM. Plates wereincubated at 37° C. for 180 min.

Following 180 min incubation, detection reagents were made up bycombining 1 part Galacton Star Substrate with 5 parts Emerald II™Solution, and 19 parts of PathHunter Cell Assay Buffer, respectively.12.5 μL detection reagent was added to each well. The plates were thenincubated at room temperature for 60 min. Plates were then read onEnvision for 0.1 sec/well.

EC₅₀ determinations were made from agonist dose-response curves analyzedwith a curve fitting program using a 4-parameter logistic dose responseequation.

The GLP-1R internalization dose-response curves for selected compoundsof the present disclosure, as compared to GLP-1 (7-37) as a control,were shown in FIG. 2 . The tested compounds include Compounds 74-80,93-95, 100, and 101 (left panel), and Compounds 81-91 (right panel).Again, the partial maximum relative effect B_(max) (at the highestconcentration tested in the assays) for the tested compound generallyapproaches about 20-30% of the B_(max) for the natural ligand GLP-1(7-37).

Using this assay system, β-Arrestin-mediatd GLP1R internalization wasalso measured for other selected compounds of the present disclosure,and the results are compiled in the table below.

β-Arrestin Internalization As Measured by PathHunter U20S Cell-basedAssay

β-arrestin β-arrestin Compound internalization Compound internalizationNo. B_(max) (POC)* No. B_(max) (POC)*  74 17.0 (n = 1) 247 26.6 (n = 1) 75 20.8 ± 10.2 (n = 2) 262 25.4 ± 1.39 (n = 2)  76 21.6 (n = 1) 26619.9 ± 0.122 (n = 2)  77 22.5 (n = 1) 267 30.2 ± 6.53 (n = 2)  78 7.49(n = 1) 276 26.7 (n = 1)  79 9.25 (n = 1) 277 23.0 (n = 1)  80 21.2 (n= 1) 278 36.5 (n = 1)  81 30.6 (n = 1) 281 36.5 (n = 1)  82 13.8 (n = 1)290 21.6 ± 3.52 (n = 2)  83 27.8 (n = 1) 291 22.8 ± 0.142 (n = 2)  8424.7 (n = 1) 292 29.6 (n = 1)  85 29.5 (n = 1) 303 28.4 (n = 1)  86 41.8(n = 1) 307 33.8 ± 2.73 (n = 2)  87 23.9 (n = 1) 308 48.8 ± 6.11 (n = 2) 88 29.2 (n = 1) 311 26.7 ± 4.53 (n = 2)  89 20.0 (n = 1) 312 45.2 (n= 1)  90 21.6 (n = 1) — —  91 21.6 (n = 1) — —  93 41.0 (n = 1) — —  9427.3 ± 7.75 (n = 2) — —  95 23.1 (n = 1) — — 100 0.881 (n = 1) — — 1013.08 (n = 1) — — *This value stands for averaged B_(max) whereapplicable (POC, or Percentage of Control).

Again, note that in each case, with few exceptions, the partial maximumrelative effect B_(max) (at the highest concentration tested in theassays) for the tested compounds generally fall within about 10% toabout 40% of the B_(max) for the natural ligand GLP-1 (7-37).

Biological Example 2: NanoBit GLPIR/β-Arrestin Interaction Assay forDemonstrating Small Molecule Compounds-Mediated GLP1R and β-ArrestinInteraction Activation

GLP-1R-mediated interaction with β-Arrestin by agonist activity isdetermined with a cell-based functional assay, utilizing a NanoLuc®Binary Technology (NanoBiT) (Promega N2015) designed to detect GLP-1Rand β-Arrestin interaction in a living cell. The method is a two-subunitsystem based on NanoLuc® luciferase that can be used for intracellulardetection of protein: protein interactions (PPIs). The two subunits areknown as the Large BiT (LgBiT; 17.6 kDa) and the Small BiT (SmBiT; 11amino acids). These two subunits are fused to two proteins of interest,respectively. When both are expressed, the PPI brings the subunits intoclose proximity to form a functional enzyme that generates a bright,luminescent signal.

More specifically, the human GLP-1R coding sequence (NCBI ReferenceSequence NM_002062) and β-Arrestin2 coding sequence (NCBI ReferenceSequence NM_004313.3) were subcloned into transient expression vectorsprovided in the NanoBiT kit, such that GLP-1R-LgBiT andSmBiT-β-Arrestin2 fusions were generated. A total of 8 combinations wereselected using HEK293T-based transfection with activation by the naturalligand GLP-1₇₋₃₇. The combination showed the highest assay window(GLP-1R-LgBiT and SmBiT-β-Arrestin2) was selected for testing thecompounds of the present disclosure.

The NanoBit assay was performed as briefly described herein: HEK293Tcells (7.5 k cells/well) were seeded in 96-well culture plate (CorningCat #3917) in DMEM (Thermo Cat #11965) with 10% FBS (Biosera Cat#FB-10581) that was heat inactivated, and 25 mM glucose. After 48 hours,cells were transfected with the GLP-1R-LgBiT and SmBiT-β-Arrestin2constructs using Lipofectamine2000 (Thermo Cat #11668019) following themanufacturer's assay protocol. Briefly, plasmids encoding theGLP-1R-LgBiT and SmBiT-β-Arrestin2 fusions, and transfection reagentwere diluted with Opti-MEM (Thermo Cat #31985-070). Then about 50 ng ofGLP-1R-LgBiT and 50 ng of SmBiT-β-Arrestin2 plasmid constructs weremixed, and the resulting plasmids mixture was added into dilutedtransfection reagent. The ratio of plasmid (μg): Lipofectamine2000 (pi)was 1:10. The mixtures were then added into cells after 5 minutes'incubation at room temperature. About 48 hours after transfection,medium was replaced by 65 μl/well fresh Opti-MEM.

Nano-Glo® Live Cell Substrate was then diluted with Nano-Glo® LCSDilution Buffer at 1:24 ratio. About 25 μl of Nano-Glo® Live CellReagent was added into each well. Varying concentrations of each subjectcompound to be tested (in DMSO) were diluted in Opti-MEM with 0.1% BSA(Sigma Cat #A7409) to make 10×stocks. About 10 μl compound stocks wereadded into each well using pipette. Luminescence was measuredimmediately by EnVision for 40, 60, or 120 repeats, with 0.25 secondsper well.

EC₅₀ determinations were made from agonist dose-response curves analyzedwith a curve fitting program using a 4-parameter logistic dose responseequation.

The effect of a small molecule compound, such as one of the instantpresent disclosure, on the GLP-1R/β-Arrestin interaction activation, orβ-Arrestin recruitment, can be demonstrated and measured using the assayand commercial reagents described herein or equivalents thereof. Thereagents and detailed experimental protocols used in this example arefurther described below.

Preparations

Reagents and Consumables:

Reagent Vendor Catalog No. NanoBiT ® Protein: Protein Promega N2015Interaction System Opti-MEM ™ I Reduced Serum Thermo Fisher 31985-070Medium Lipofectamine ™ 2000 Thermo Fisher 11668019 Transfection ReagentHuman GLP-1-(7-36)-amide MCE HY-P0054A 96 well plates, white Corning3917 DMEM Thermo Fisher 11965 Fetal Bovine Serum Biosera FB-10581/500DMSO Sigma D2650Instruments:

Instrument Vendor Internal Code En Vision PerkinElmer HD-4HYSG2330Preparation of the Nano-Glo® Live Cell Reagent:

-   1. Equilibrate Nano-Glo® LCS Dilution Buffer to ambient temperature    if using for the first time.-   2. Remove the Nano-Glo® Live Cell Substrate from storage and mix.-   3. Prepare the desired amount of reconstituted Nano-Glo® Live Cell    Reagent by combining 1 volume of Nano-Glo® Live Cell Substrate with    24 volumes of Nano-Glo® LCS Dilution Buffer (a 25-fold dilution),    creating a 4× stock to mix with cell culture medium.    Procedures    Compound Preparation:

GLP-1 (7-36) is dissolved in 100% DMSO and the stock concentration is 1mM.

HPE: 10 μM GLP-1 (7-36)

ZPE: 0.1% DMSO

For test compounds, dilute 1 mM stock to 100 μM using Opti-MEMcontaining 1% BSA, final top concentration is 10 μM, ¼ log (4-fold)dilution, 8-dilution points, duplicate samples for each dilution. Thelayout is similar to GLP-1 above.

Assay Procedure:

Cell Culture and Transfection:

-   -   1. Seed 7.5 k cells/well 293T cells in 96 well culture plate        (Corning #3917) in the DMEM with 10% FBS (heat inactivated and        25 mM glucose).    -   2. After 48 hours, performance transfection according to        protocol of Lipofectamine2000.    -   3. 50 ng Lg-Bit and 50 ng Sm-Bit/well, the ratio of plasmid        (μg): Lipofectamine2000 (pi) is 1:10.    -   4. 48 hours later after transfection, medium was replaced by        fresh 65 μL Opti-MEM/well.        Activation and Luminescence Measurement:    -   5. Prepare Nano-Glo® Live Cell Reagent, diluted Nano-Glo® Live        Cell Substrate with Nano-Glo® LCS Dilution Buffer in 1:24 ratio.    -   6. Add 25 μL Nano-Glo® Live Cell Reagent into each well.    -   7. Add 10 μL 10% DMSO or 10×GLP-1 solutions or test compounds        into each well.    -   8. Immediately measure luminescence for 40, 60, or 120 repeats,        with 0.25 seconds/well.

As shown in FIG. 3 , the NanoBit assay time-course responses atdifferent compound concentrations are plotted for GLP-1 (7-37) andCompound 94 (FIG. 3 ).

The results clearly show that the time-course profiles are quitedifferent between the natural ligand GLP-1 (7-37) and the testedcompounds of the present disclosure.

NanoBit assay dose response curves for the 3 min (180 sec) and 5 min(300 sec) time points were also generated for additional test compounds,including Compounds 74-91, 93-95, 100, and 101 (FIG. 4 ). In each ofthese figures, the maximum relative effects for the tested compoundsE_(max), for the highest concentrations tested, are generally no morethan 40% (usually about 20-40%) of that of GLP-1 (7-37).

EC50 values for Compounds 74-91, 93-95, 100 and 101 were determined(data not shown).

As an alternative, data analysis/report to obtain EC50 values can bedone when compounds reach maximal signals—such as at 450-500 sec (˜8min).

Biological Example 3 GLP1R cAMP Assay for Demonstrating Small MoleculeCompounds-Mediated GLP-1R Activation

HEK293/GLP-1R/CRE/Luc, Clone 4—cAMP Assay

GLP-1R-mediated agonist activity was determined with a cell-basedfunctional assay utilizing an HTRF (Homogeneous Time-ResolvedFluorescence) cAMP detection kit (cAMP Dynamic 2 Assay Kit; CisBio cat#62AM4PEC) that measures cAMP levels in the cell. The method is acompetitive immunoassay between native cAMP produced by the cells andexogenous cAMP labeled with the dye d2. The tracer binding is visualizedby a mAh anti-cAMP labeled with Cryptate. The specific signal (i.e.,energy transfer) is inversely proportional to the concentration of cAMPin either standard or experimental sample.

The human GLP-1R coding sequence (NCBI Reference Sequence NM_002062) wassubcloned into pcDNA3.1+/Hygro vector (Invitrogen) and transfected intoHEK293/CRE/Luc parental cell line. A cell line stably expressing thereceptor was isolated. Saturation binding analyses (filtration assayprocedure) using ¹²⁵I-GLP-1₇₋₃₆ (Perkin Elmer) shows that plasmamembranes derived from this cell line express a high GLP-1R density (K₄:<1 nM, B_(max): >800 fmol/mg protein).

Varying concentrations of each compound to be tested (in DMSO) werediluted in DMSO to obtain 200× compound working solution first and then50 nl compounds were added to a white 384-well assay plate (Greiner784075) with ECHO. The final DMSO concentration was 0.5%. The compoundconcentration range may be adjusted at any time.

Cells were removed from cryopreservation, re-suspended in 5 mL ofDulbecco's Phosphate Buffered Saline (DPBS-Sigma Cat #D8537) andcentrifuged at 900/g for 5 min at 22° C. The cell pellet was thenre-suspended in 1 mL of assay buffer [DPBS with 500 μM IBMX (Sigma#15879) and 0.1% BSA (Sigma #A1933). IBMX and BSA were freshly added onthe day of assay]. A 10 μL sample of the cell suspension was counted onan Invitrogen Countess II to determine cell viability and cell count permL. The remaining cell suspension was then adjusted with assay buffer todeliver 1000 viable cells per well using a Matrix Combi Multidropreagent dispenser. 10 μL cell suspensions were added to each well

of the assay plate which already contains compound. The plate was sealedand incubated at 37° C. with 5% CO₂ for 30 minutes.

Following the 30 minute incubation, 5 μL of labeled d2 cAMP and 5 μL ofanti-cAMP antibody (both diluted 1:20 in cell lysis buffer; as describedin the manufacturer's assay protocol) were added to each well of theassay plate. The plates were then incubated at room temperature andafter 60 minutes, changes in the HTRF signal were read with an Envisionmulti-label plate reader using excitation of 330 nm and emissions of 615and 665 nm. Raw data were converted to nM cAMP by interpolation from acAMP standard curve (as described in the manufacturer's assay protocol)and the percent effect was determined relative to a saturatingconcentration of the full agonist GLP-1₇₋₃₇ (10 nM) included on eachplate. EC₅₀ determinations were made from agonist dose-response curvesanalyzed with a curve fitting program using a 4-parameter logistic doseresponse equation.

This assay demonstrates that the compounds of the present disclosureactivates GLP-1R signaling through the cAMP pathway, thus behave asGLP-1R agonists. The representive commercial reagents/kits that can be(were) used in such assays are described below.

Preparations

Reagents and Consumables:

Reagent Vendor Catalog No. HEK/GLP1R/CRE/Luc cell line HDB DMEM Gibco12100 Exendin (9-39) MCE HY-P0264 Human GLP-1-(7-37)-amide MCE HY-P0055384 well plates, white Greiner 784075 cAMP dynamic 2 Cisbio 62AM4PECFetal Bovine Serum Biosera FB-10581/500 IBMX Sigma 15879 BSA SigmaA1933-5G DPBS Sigma D8537Instruments:

Instrument Vendor Internal Code EnVision PerkinElmer HD-4HYSG2330Media and Solutions:

1) Assay Buffer

DPBS with 500 μM IBMX and 0.1% BSA. IBMX and BSA are freshly added onthe day of assay.

2) cAMP-d2 working solution preparation

-   -   a) The lyophilisate was reconstituted with an appropriate amount        of distilled water according to manufacturer's instructions to        make working stock which can be aliquoted and frozen (−20° C.).    -   b) The working stock solution was diluted 1:20 in the conjugate        and lysis buffer before use.

3) Anti-cAMP antibody-cryptate working solution preparation

-   -   c) The lyophilisate was reconstituted with appropriate amount of        distilled water according to manufacturer's instruction to make        working stock which can be aliquoted and frozen (−20° C.).    -   d) The working stock solution was diluted 1:20 in the conjugate        and lysis buffer before use.        Procedures        Procedures for Cell Suspension Preparation    -   1. Frozen cells were thawed very briefly in a 37° C. water bath        under sterile conditions until just before ice completely melt        (for about 1 minute) with a continuous agitation. Caution was        taken because a longer incubation could result in cell death.    -   2. DMSO was removed from the media by carefully transferring        thawed cells to a sterile 15/50 mL tube, filling a tube with        10-50 mL of complete media pre-warmed to 37° C., and allowing        the cells to sit 5 min before centrifuging at 900 rpm for 5        minutes for cell collection.    -   3. The cells were resuspended with assay buffer.    -   4. For stable GLP1-R assay, the optimized cell density is 1000        cells/well. Caution was taken because cell density optimization        was crucial and needed to be optimized in different        labotatories. The level of cAMP produced by the cells must fall        within the linear range of the standard curve.        Procedures for Compound Preparation    -   1) Reference agonist compound GLP1 (7-37) was dissolved with        DMSO to make a 1 mM stock solution, which was then aliquoted and        stored at −80° C.    -   2) Reference antagonist compound Exendin (9-39) was dissolved        with DMSO to make a 2 mM stock solution, which was then        aliquoted and stored at −80° C.    -   3) Test compounds were dissolved with DMSO to make stock        solutions, aliquoted and stored at −80° C. Serial dilutions of        compound solutions were made using DMSO to obtain a 200×        compound working solution first and then 50 nL of the working        solution to 384-well plate with ECHO. The final DMSO        concentration is 0.5%. The compound concentration range may be        adjusted at any time.    -   4) IBMX: 500 mM stock solution dissolved in DMSO, aliquot and        stored at −20° C.        Procedures for Agonist Assay    -   1) Compound preparation: compound addition plates were prepared        in advance of the assay. 200× compound working solutions were        prepared according to procedures described above.    -   2) Cell preparation: cell suspensions were prepared according to        procedures described above before running the assay.    -   3) Compound addition: 50 nL/well of 200/compound working        solutions were added to low-volume 384 white assay plate with        Echo.    -   4) Cell addition: 10 μL cell suspensions were added to each well        of the assay plate which already contained the compound working        solution. The plate was sealed and incubated at 37° C. with 5%        CO₂ for 30 minutes.    -   5) 5 μL of a cAMP-d2 working solution was added to each well of        the assay plate.    -   6) 5 μL of an anti-cAMP antibody-cryptate working solution was        added to each well of the assay plate. The plate was covered        with a lid. Incubate at room temperature for 1 hours.    -   7) The fluorescence was read at 665 and 615 nm with an EnVision        plate reader with TRF LASER using the specified settings and the        data was saved.        Procedures for Antagonist blocking Assay    -   1) Compound preparation: prepare compound addition plates in        advance of assay. Prepare 200×concentration of compound working        solutions according to procedures described above.    -   2) Cell preparation: cell suspensions are prepared according to        procedures described above before running the assay.    -   3) Compound addition: add 50 nL/well of working concentration of        200× compound to low-volume 384 white assay plate.    -   4) Cell addition: Add 5 μL of 2× cell suspensions to each well        of the assay plate which already contains compound.    -   5) Exendin (9-39) Antagonist addition: Add 5 μL of 2× Exendin        (9-39) to each well of the assay plate which already contains        compound and cells. The final concentration of Exendin (9-39) is        IC80. Seal the plate and incubate at 37° C. with 5% CO2 for 30        minutes.    -   6) Add 5 μL cAMP-d2 working solution to each well of the assay        plate.    -   7) Add 5 μL Anti-cAMP antibody-cryptate working solution to each        well of the assay plate. Cover the plate with lid. Incubate at        room temperature for 1-4 hours.    -   8) Read the fluorescence at 665 and 615 nm with EnVision plate        reader with TRF LASER using the specified settings and save        data.        Setting up EnVision for HTRF cAMP Measurements        Required Filters and Mirrors    -   Excitation: TRF LASER    -   Emission #1: 665 nm (CWL 665 nm BW 7.5 nm)    -   Emission #2: 615 nm (CWL 615 nm BW 8.5 nm)    -   Dichroic mirror: DELFIA/LANCE Dual Enh D400/D630        Required Settings:    -   Delay: 50 μs    -   Window Time: 300 μs (also called “integration time”)    -   Number of sequence windows: 1    -   Cycle: Default 2000 μs (also called “time between flashes”)    -   Time between flashes: 2000 μs    -   number of flashes: 20    -   number of flashes for 2nd detector: 10    -   measurement height (mm): 6.5    -   Z height: Must be optimized (use optimization Wizard, optimize        on a well with maximum FRET)    -   Excitation and Emissions are done on the top of the well        cAMP Assay Data Processing

Data analysis: GraphPad Prism 5 or IDBS XLfit software is used forestablishment of progression curve. EC50s or IC50s were determined by4-parameter logistic dose response equation.

Using the assay substantially as described above, dose-response curvefor each compound tested below were obtained, and their respective EC₅₀values calculated and tabulated. Here, EC₅₀ value for each compound isdefined as the compound concentration that yielded 50% of the maximumcAMP level achieved with the same compound.

Final compound concentration is 10, 100, or 300 nM in 0.5% DMSO. A totalof 11 data points were generated for each compound serial dilution.

The cAMP assay results for Compounds 75, 84, 93, 94, and GLP-1(7-37) ascontrol, are shown in FIG. 5 .

Two different cell types were used for this assay. In one assay, eachcompound was tested in HEK293T cells. The results are shown below inTable 1. In another assay, selected compounds were also tested in CHOcells that have been stably transfected to express human GLP-1R. Theresults are shown below in Table 2.

TABLE 1 Compound EC₅₀ Values in HEK293T Cells EC₅₀ EC₅₀ A = ≤0.015 μM A= ≤0.015 μM B = ≤0.15 μM B = ≤0.15 μM Compound C = ≤1 μM Compound C = ≤1μM # D = >1 μM # D = >1 μM  74 A 246 B  75 A 247 A  76 A 248 D  77 A 249B  78 A 250 B  79 B 251 B  80 A 252 B  81 A 253 B  82 A 254 B  83 A 255B  84 A 256 B  85 A 257 A  86 A 258 A  87 A 259 A  88 A 260 A  89 A 261A  90 A 262 A  91 A 263 A  92 A 264 A  93 A 265 A  94 A 266 A  95 A 267A  96 A 268 A  97 A 269 A  98 A 270 A  99 A 271 A 100 D 272 A 101 D 273A 102 A 274 A — — 275 A — — 276 A — — 277 A — — 278 A — — 279 A — — 280A — — 281 A — — 282 A — — 283 A — — 284 A — — 285 A — — 286 A — — 287 A— — 288 A — — 289 A — — 290 A — — 291 A — — 292 A — — 293 A — — 294 A —— 295 A — — 296 A — — 297 A — — 298 A — — 299 A — — 300 A — — 301 A — —302 B — — 303 A — — 304 A — — 305 A — — 306 A — — 307 A — — 308 A — —309 A — — 310 A — — 311 A — — 312 A — — 313 A — — 314 B — — 315 C — —316 B — — 317 A — — 318 B — — 319 B — — 320 B — — 321 B — — 322 A — —323 A — — 324 B — — 325 B — — 326 B — — 327 B — — 328 B — — 329 B — —330 A — — 331 A — — 332 A — — 333 B — — 334 A

TABLE 2 Compound EC₅₀ Values in CHO Cells Stably Expressing hGLP-1R CHOcAMP CHO cAMP stable EC₅₀ stable EC₅₀ A = ≤0.015 μM A = ≤0.015 μM B =≤0.15 μM B = ≤0.15 μM Compound C = ≤1 μM Compound C = ≤1 μM # D = >1 μM# D = >1 μM  84 A  93 A 263 A 266 A 272 B 276 A 278 A 279 A 280 B 287 B288 B 292 A 294 B 296 A 298 B 300 B 301 B 303 A 310 A 311 A 312 A 322 B326 D

The data shows that, similar to GLP-1(7-37), many tested compounds havenanomolar or sub-nanomolar (<10 nM) EC₅₀ values in the cAMP assay. This,coupled with the fact that many tested compounds also have B_(max)values reaching substantially the same level of that for GLP-1(7-37),suggests that many of the tested compounds of the present disclosure arefull agonists of the GLP-1R signaling leading to cAMP production.

In contrast, as shown in Examples 1 and 2 above, particularly the datafor the compounds listed in the tables, the compounds of the presentdisclosure generally have B_(max) approaching about 20-40% of that ofGLP-1 (7-37) in the β-Arrestin recruitment assay and GLP-1Rinternalization assay, though a few exceptions exist. Further, theNanoBit time course profiles are different between the compounds of thepresent disclosure and those of GLP-1(7-37).

Example 4 Compound Synthesis(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 74)

Step 1. Synthesis of methyl 2-(4-bromo-3-fluorophenyl)acetimidate

To a mixture of 1 2-(4-bromo-3-fluoro-phenyl)acetonitrile (4.24 g, 19.8mmol), methanol (600 mg, 19.8 mmol) and 1,4-dioxane (20 mL) in a Schlenktube was bubbled HCl gas, until the completion of the reaction. Thereaction mixture was filtered to afford the title compound methyl2-(4-bromo-3-fluorophenyl)acetimidate (2) (4.2 g, 17.1 mmol, 86.2%yield) as a white solid.

Step 2. Synthesis of 1-bromo-2-fluoro-4-(2,2,2-trimethoxyethyl)benzene

A mixture of 2 from above (2.1 g, 8.53 mmol) in methanol (20 mL) wasstirred for 18 h in a Schlenk tube under an atmosphere of N₂. Thereaction was monitored by TLC and LCMS. The reaction mixture wasconcentrated in vacuo, and then EtOAc was added to reaction mixtureuntil large quantities of solid precipitated out. The solid was filteredout, the filtrate was concentrated to afford the title compound1-bromo-2-fluoro-4-(2,2,2-trimethoxyethyl) benzene as a crude product(3) (1.8 g, 6.14 mmol, 72% yield) as a colorless oil.

Step 3. Synthesis of methyl(S)-2-(4-bromo-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

A mixture of 3 from above (297.8 mg, 1.02 mmol), p-TSA (100 mg, 0.63mmol) and methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate 4(150 mg, 0.63 mmol) in acetonitrile (15 mL) was stirred for 2 h in aSchlenk tube under an atmosphere of N₂ and then moved to an oil bath at85° C. and stirred for 3 h, until the reaction was completed asindicated by TLC. The reaction mixture was concentrated in vacuo,purified by SGC (hexanes/EtOAc=5:1-1:1) to give the title compoundmethyl(S)-2-(4-bromo-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(5) (180 mg, 0.42 mmol, 65.4% yield) as a yellow solid.

Step 4. Synthesis of methyl(S)-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

A mixture of 5 from above (220 mg, 0.51 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(154.7 mg, 0.61 mmol) and KOAc (124.6 mg, 1.27 mmol) and Pd(dppf)Cl₂(37.2 mg, 0.051 mmol) in 1,4-dioxane (5 mL) in a Schlenk tube under anatmosphere of N₂. The reaction tube was sealed, moved to an oil bath at90° C. and stirred for 3 h, the reaction was complete as indicated byTLC and LCMS. The reaction mixture was filtered and the solution ofcrude product methyl(S)-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(6) (280 mg, 0.41 mmol, 80.4% yield, 70% purity) was used to next step.LCMS: [M+H]⁺=480.0.

Step 5. Synthesis of methyl(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

A mixture of 7 (30 mg, 0.095 mmol), Pd(dppf)C₁₋₂ (7.7 mg, 0.0095 mmol)and K₂CO₃ (39.3 mg, 0.28 mmol) and crude product of 6 from above (68.3mg, 0.14 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was stirred for 3h in a Schlenk tube under an atmosphere of N₂. The reaction tube wassealed, moved to an oil bath at 100° C. and stirred for 3 h, thereaction was complete as indicated by TLC and LCMS. The reaction mixturewas filtered and crude product was purification by TLC to give the titlecompound methyl(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(8) (9 mg, 0.015 mmol, 17.9% yield). LCMS: [M+H]⁺=590.1.

Step 6. Synthesis of(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid

A mixture of 8 from above (9 mg, 0.015 mmol), LiOH (3.7 mg, 0.15 mmol)in methanol (3 mL) was stirred for 3 h in a Schlenk tube under anatmosphere of N₂ at 25° C., the reaction as indicated by TLC and LCMS.The reaction mixture was adjusted with AcOH to pH=7.0. Then the crudeproduct was purified by prep-HPLC to give the title compound(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (3.3 mg, 0.006 mmol, 37.6% yield, 100% purity) as a white solid.LCMS: [M+H]⁺=576.1.

(S)-2-(4-(6-(4-cyano-2-fluorobenzyloxy)pyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 75)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS: [M+H]⁺=567.3.

(S)-2-((3′-((4-chloro-2-fluorobenzyl)oxy)-2-fluoro-[1,1′-biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 76)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS [M+H]⁺=575.2.

(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)-3f-difluoropyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 77)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS: [M+H]⁺=611.8.

(S)-2-((3′-((4-chloro-2-fluorobenzyl)oxy)-2,4′-difluoro-[1,1′-biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 78)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS: [M+H]⁺=593.1.

(S)-2-((5′-((4-chloro-2-fluorobenzyl)oxy)-2,2′-difluoro-[1,1′-biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 79)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS: [M+H]⁺=593.0.

(S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 80)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS [M+H]⁺=576.1.

(S)-2-(4-(4-(4-chloro-2-fluorobenzyloxy)-5-fluoropyrimidin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 81)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS: [M+H]⁺=594.9.

(S)-2-(4-(2-(4-chloro-2-fluorobenzyloxy)-5-fluoropyrimidin-4-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 82)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS [M+H]⁺=595.2.

(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 83)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS: [M+H]⁺=594.0.

(S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 84)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS: [M+H]⁺=567.0.

(S)-2-((3′-((4-chloro-2-fluorobenzyl)oxy)-3,4′-difluoro-[1,1′-biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid) (Compound 85)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS: [M+H]⁺=593.0.

(S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 86)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS [M+H]⁺=576.9.

(S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 87)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS [M+H]⁺=576.9.

(S)-2-(4-(6-(4-chloro-2-fluorobenzyloxy)-5-fluoropyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 88)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS [M+H]⁺=594.1.

(S)-2-((3′-((4-chloro-2-fluorobenzyl)oxy)-3-fluoro-[1,1′-biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid(Compound 89)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS: [M+H]⁺=575.0.

(S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrunidin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 90)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS [M+H]⁺=594.9.

(S)-2-(4-(2-(4-chloro-2-fluorobenzyloxy)-5-fluoropyrimidin-4-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 91)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS: [M+H]⁺=595.0.

(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)-3-fluoropyrimidin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 92)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS: [M+H]⁺=594.8.

(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 93)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS: [M+H]⁺=576.2.

(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 94)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS: [M+H]⁺=558.0.

(S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 95)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS: [M+H]⁺=549.2.

(S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 96)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS [M+H]⁺=577.0.

(S)-2-(4-(6-(4-chloro-2-fluorobenzyloxy)-3-fluoropyrimidin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 97)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS [M+H]⁺=594.1.

(S)-2-(4-(6-(4-chloro-2-fluorobenzyloxy)-3f-difluoropyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-benzo[d]imidazole-5-carboxylicacid (Compound 98)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS: [M+H]⁺=612.0.

(S)-2-(2-chloro-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 99)

The title compound was prepared analogously as for Compound 74 as awhite solid. LCMS: [M+H]⁺=593.1.

(S)-2-((6′-(4-chloro-2-fluorobenzyloxy)-2,2′-bipyridin-5-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 100)

Step 1. Synthesis of methyl 2-(6-bromo-3-pyridyl)ethanimidate

To a mixture of 2-(6-bromo-3-pyridyl)acetonitrile 1 (985 mg, 5.0 mmol),methanol (0.30 mL, 7.5 mmol) in dioxane (20 mL) was bubbled HCl (gas)with stirred for 6 h at rt in a round bottom flask, until the reactionwas completed as indicated by LCMS, the reaction mixture wasconcentrated in vacuo to give the desired product methyl2-(6-bromo-3-pyridyl)ethanimidate (2) (1.4 g, crude) as white solid.LCMS: (M+H)⁺=230.0.

Step 2. Synthesis of 2-(6-bromo-3-pyridyl)acetic acid

A mixture of 2 from above (1.2 g, 5.24 mmol), Cone. HCl (10 mL) in Water(10 mL) was stirred for 1 h at 100° C. in a round bottom flask-under N₂,until the reaction was completed as indicated by LCMS, the reactionmixture was concentrated in vacuo to give the desired product2-(6-bromo-3-pyridyl)acetic acid (9) (0.68 g, crude) as pale yellowsolid. LCMS: (M+H)⁺=217.9.

Step 3. Synthesis of methyl methyl(S)-4-(2-(6-bromopyridin-3-yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate

A mixture of 9 from above (216 mg, 999.9 umol),di(imidazol-1-yl)methanone (162.1 mg, 1.0 mol) in THF (20 mL) wasstirred for 0.5 h at 50° C., then methyl4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (4) (236.2 mg, 1.0mmol) was added to the mixture, it was stirred for another 2.5 h underN₂, until the reaction was completed as indicated by LCMS, the reactionmixture was concentrated in vacuo, purified by prep-HPLC to give thedesired product methyl methyl(S)-4-(2-(6-bromopyridin-3-yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate(10) (180 mg, 0.42 mol, 41.5% yield) as white solid. LCMS: (M+H)⁺=435.9.

Step 4. Synthesis of methyl(S)-2-((6-bromopyridin-3-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

A mixture of 10 from above (180 mg, 0.41 mmol) in acetic acid (10 mL)was stirred for 0.5 h at 120° C. in a round bottom flask under N₂, untilthe reaction was completed as indicated by LCMS, the reaction mixturewas concentrated in vacuo, dried in vacuo to give the desired productmethyl(S)-2-((6-bromopyridin-3-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(11) (170 mg, crude) as pale yellow solid. LCMS: (M+H)⁺=416.0.

Step 5. Synthesis of 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine

A mixture of (4-chloro-2-fluoro-phenyl)methanol 12 (8.0 g, 49.8 mmol),2-bromo-6-fluoro-pyridine (8.77 g, 49.8 mmol, 5.13 mL),1,4,7,10,13,16-hexaoxacyclooctadecane (658.4 mg, 2.5 mmol, 0.56 mL), KOH(4.19 g, 74.7 mmol) in Toluene (100 mL) was stirred for 18 h at rt in around bottom flask under N₂, until the reaction was completed asindicated by LCMS, the reaction mixture was extracted with 50 mL ofEtOAc 3 times, the combined organic layers were washed by brine, driedover Na₂SO₄, and concentrated in vacuo, purified by silica gelchromatography (Hexanes/EtOAc=20:1) to give the desired product2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine (13) (15 g, 47.4 mmol,95.1% yield) as white solid. LCMS: (M+H)⁺=316.0.

Step 6. Synthesis of2-((4-chloro-2-fluorobenzyl)oxy)-6-(tributylstannyl)pyridine

To the mixture of 13 from above (1.58 g, 4.99 mmol) in THF (20 mL) wasadded n-butyllithium (383.7 mg, 5.99 mmol, 2.4 mL) stirred for 3 h at−70° C. in a round bottom flask under N₂, then Bu₃SnCl (2.44 g, 7.49mmol, 2.03 mL) was added to the mixture, after addition the mixture wasallowed to warm to rt for another 2 h, the reaction was completed asindicated by LCMS, the reaction mixture was quenched with saturatedNH₄Cl in an ice bath, dried over Na₂SO₄, the organics were concentratedin vacuo to give the desired product2-((4-chloro-2-fluorobenzyl)oxy)-6-(tributylstannyl)pyridine (14) (3.5g, crude) as pale yellow liquid, which was directly use to the nextstep.

Step 7. Synthesis of methyl(S)-2-((6′-((4-chloro-2-fluorobenzyl)oxy)-[2,2′-bipyridin]-5-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

A mixture of 11 (150 mg, 0.35 mmol), 14 (189.8 mg, 0.36 mmol),Pd(PPh₃)₂C₁₋₂ (34 mg, 0.029 mol), CuI (34 mg, 0.178 mol, 6.05 uL) in DMF(5 mL) was stirred for 1 h at 90° C. in a RBF under N₂, until thereaction was completed as indicated by LCMS, the reaction mixture wasfiltered and purified by prep-HPLC to give the desired product methyl(S)-2-((6′-((4-chloro-2-fluorobenzyl)oxy)-[2,2′-bipyridin]-5-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(15) (40.0 mg, 0.070 mmol, 19.4% yield) as pale yellow solid. LCMS:(M+H)⁺=573.0.

Step 8. Synthesis of(S)-2-((6′-((4-chloro-2-fluorobenzyl)oxy)-[2,2′-bipyridin]-5-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid

A mixture of 15 from above (40.0 mg, 0.070 mmol) and LiOH (117.2 mg,2.79 mmol, 77.6 uL) in methanol (1 mL), Water (1 mL), THF (1 mL) wasstirred for 1 h at rt in a RBF under N₂, until the reaction wascompleted as indicated by LCMS, the reaction mixture was adjusted pH=7by HOAc, the mixture was purified by prep-HPLC to give the titlecompound(S)-2-((6′-((4-chloro-2-fluorobenzyl)oxy)-[2,2′-bipyridin]-5-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (6.9 mg, 0.012 mmol, 17.7% yield) as white solid. LCMS:(M+H)⁺=558.9.

(S)-2-((6-((4-chloro-2-fluorobenzyl)oxy)-[2,3′-bipyridin]-6′-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 101)

The title compound was prepared in analogous manner as for Compound 100as a white solid. LCMS: (M+H)⁺=558.9.

(S)-2-(4-(6)-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 102)

Step 1. Synthesis of 6-chloro-5-nitropicolinic acid

To a stirred solution of 2-chloro-6-methyl-3-nitro-pyridine 16 (4.0 g,23.2 mmol) in sμLfuric acid (16 mL) at room temperature was addedK₂Cr₂O₇ (10.2 g, 34.8 mmol). The reaction mixture was stirred at 30° C.for 24 h and upon completion of the reaction, as judged by LCMS, themixture was diluted with Water (200 mL) under ice bath, The resμLtantprecipitates were filtered and washed with water (20 mL) and dried underreduced pressure to afford 6-chloro-5-nitropicolinic acid 17 (3.9 g,19.3 mmol, 83.3% yield, 100% purity) as a light-yellow solid. LCMS:[M+H]⁺=203.

Step 2. Synthesis of methyl 6-chloro-5-nitropicolinate

To a suspension of 17 from above (3.9 g, 19.3 mmol) in Dichloromethane(40 mL) was added oxalyl dichloride (4.9 g, 38.5 mmol, 3.35 ml) andN,N-dimethylformamide (0.23 ml) at 0° C. The reaction mixture wasstirred at 25° C. for 1 h. Methanol (2.37 g, 74.1 mmol, 3 mL) was addedto the reaction mixture at 25° C. The solution was stirred at 25° C. foran additional 60 min. The mixture was concentrated in vacuo to give theresidue, which was purified by flash chromatography (Biotage, 80 gsilica gel column at 100 mL/min, eluting with 0-60% ethyl acetate inpetroleum ether for 30 min) to afford methyl 6-chloro-5-nitropicolinate18 (2.63 g, 12.1 mmol, 63.1% yield, 100% purity) as a white solid. LCMS[M+H]⁺=217.

Step 3. Synthesis of methyl(S)-5-nitro-6-((oxetan-2-ylmethyl)amino)picolinate

To a stirred solution of [(2S)-oxetan-2-yl]methanamine (663.7 mg, 7.6mmol) and 18 from above (1.50 g, 6.9 mmol) in DMF (23 ml) at 25° C. wasadded N-ethyl-N-isopropyl-propan-2-amine (2.69 g, 20.8 mmol, 3.62 ml).The reaction mixture was stirred at 25° C. for 16 h and upon completionof the reaction, as judged by LCMS, the mixture was diluted with EtOAc(100 mL) and warmed to room temperature. The layers were separated, andthe aqueous layer was extracted with EtOAc (2×100 ml). The combinedorganic phase was washed with brine (100 ml) and dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude product waspurified by flash column chromatography (SiO₂, Petroleum ether/ethylacetate=0˜40%) to afford methyl(S)-5-nitro-6-((oxetan-2-ylmethyl)amino)picolinate 19 (1.80 g, 6.5 mmol,93.3% yield, 96% purity) as a yellow solid. LCMS: [M+H]⁺=267.

Step 4. Synthesis of methyl(S)-5-amino-6-((oxetan-2-ylmethyl)amino)picolinate

To a stirred solution of 19 from above (1.8 g, 6.7 mmol) inHexafluoroisopropanol (25 mL) at 25° C. was added 10% Pd/C (304 mg). Thereaction mixture was stirred at 25° C. for 4 h under hydrogen and uponcompletion of the reaction, as judged by LCMS, the mixture was dilutedwith EtOAc (100 mL), filtered and the filtrate cake was washed withEtOAc (2×100 mL). The combined organic phase concentrated in vacuo toafford methyl (S)-5-amino-6-((oxetan-2-ylmethyl)amino)picolinate 20 (1.6g, 6.1 mmol, 91.1% yield, 91% purity) as a yellow solid. LCMS:[M+H]⁺=238.

Step 5. Synthesis of methyl(S)-2-(4-bromo-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate

To a stirred solution of 20 (260 mg, 1.10 mmol) in CH₃CN (8 mL) at roomtemperature was added 4-methylbenzenesμLfonic acid (41.9 mg, 0.22 mmol)and 1-bromo-2-fluoro-4-(2,2,2-trimethoxyethyl)benzene (483.7 mg, 1.7mmol). The reaction mixture was stirred at 90° C. for 2 h and uponcompletion of the reaction, as judged by LCMS, the mixture was dilutedwith EtOAc (100 mL) and cooled to room temperature. The layers wereseparated, and the aqueous layer was extracted with EtOAc (2×150 mL).The combined organic phase was washed with brine (100 mL) and dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude productwas purified by flash column chromatography (SiO2, petroleum ether/ethylacetate 5:1) to afford methyl(S)-2-(4-bromo-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate21 (180 mg, 0.41 mmol, 37.7% yield) as a white solid. LCMS: [M+H]⁺=434.

Step 6. Synthesis of methyl(S)-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate

To a stirred solution of 21 from above (20.0 mg, 0.046 mmol) and4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(14.0 mg, 55.3 mmol) in 1,4-Dioxane (1 mL) at 100° C. was addedPdCl₂(dppf) (5.1 mg) and potassium acetate (13.6 mg). The reactionmixture was stirred at 100° C. for 12 h and upon completion of thereaction, as judged by LCMS, the mixture was diluted with EtOAc (100 mL)and warmed to room temperature to concentrated in vacuo to afford crudemethyl(S)-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate22 (22 mg, 0.046 mmol, 99.2% yield) as a yellow solid, which was usedfor the next step without purification.

Step 7. Synthesis of methyl(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate

To a stirred solution of 22 from above (22.0 mg, 0.046 mmol) and 13(17.4 mg, 0.055 mmol) in 1,4-dioxane (2 mL) at 25° C. was addedPdCl₂(dppf) (1.7 mg, 0.002 mmol) and potassium carbonate (19.0 mg, 0.14mmol). The reaction mixture was stirred at 90° C. for 3 hand uponcompletion of the reaction, as judged by LCMS, the mixture was dilutedwith EtOAc (100 mL) and warmed to room temperature to concentrated invacuo, which was purified by flash column chromatography (silica gel,Petroleum ether/ethyl acetate=0-40%) to afford methyl(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate23 (20.0 mg, 0.034 mmol, 74.0% yield) as a yellow solid. LCMS:[M+H]⁺=591.

Step 8. Synthesis of(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid

To a stirred solution of 23 from above (20.0 mg, 0.034 mmol) in Water (1ml), THE (1 mL) and methanol (1 mL) at 25° C. was added Lithiumhydroxide monohydrate (2.8 mg, 0.068 mmol). The reaction mixture wasstirred at 25° C. for 1 h and upon completion of the reaction, as judgedby LCMS, the mixture was acidified with AcOH until pH˜6 and diluted withDML (3 mL) and purified by reverse phase-HPLC (Instrument: Gilson281(PHG012); Column: Xtimate C18 10 um, 21.2×250 mm; Mobile phase: A:water (10 mM NH₄HCO₃, 0.025% NH₃.H₂O), B: Acetonitrile; Gradient: 30% Bfor 1 min, then 45% B in 7 min, stop at 15 min; Plow rate: 30 mL/min;Detective wavelength: 214/254 nm; Retention time: 8.0 min; Injectionnumber: 3), the corresponding fractions were combined, concentratedunder reduced pressure to remove most of the organic solvent, and theaqueous residue was lyophilized to afford the title compound(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid as a white solid (7.0 mg, 0.012 mmol, 35.9% yield). LCMS:[M+H]⁺=577.

(S)-2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)thiazol-2-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 246)

Step 1

A mixture of 2,4-dibromothiazole (2.0 g, 8.23 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate(2.55 g, 8.23 mmol) and Pd(dppf)Cl₂ (602.42 mg, 823.32 μmol), Cs₂CO₃(5.37 g, 16.47 m mol) in 1,4-Dioxane (40 mL) was stirred for 10 h at 90°C. in a RBF under N₂, until the reaction was completed as indicated byLCMS, the reaction mixture was concentrated in vacuo, purified by silicagel chromatography (Hexanes/EtOAc=10:1, Rr=0.4) to give the desiredproduct tert-butyl4-(4-bromothiazol-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2.2 g,6.37 mmol, 77.4% yield, 100% purity) as a light yellow solid. LCMS:[M+H]+=291.0; Retention time (10 mM NH₄HCO₃)=1.79 min.

Step 2

A mixture of tert-butyl4-(4-bromothiazol-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.0 g,2.90 mmol), (4-chloro-2-fluoro-phenyl)methanol (697.6 mg, 4.34 mmol) andSphos-Pd G₃ (225.92 mg, 289.64 μmol), t-BuONa (835.1 mg, 8.69 m mol) intoluene (5 mL) was stirred for 16 hr at 60° C. in a RBF under N₂, untilthe reaction was completed as indicated by LCMS, the reaction mixturewas filtered through a pad of Celite with EtOAc, and the combinedorganics were concentrated in vacuo, purified by prep-HPLC to give thedesired product tert-butyl4-[4-[(4-chloro-2-fluoro-phenyl)methoxy]thiazol-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate(30 mg, 70.60 μmol, 2.4% yield) as yellow oil. LCMS: [M+H]⁺=425.2;Retention time (0.01% TFA)=2.49 min.

Step 3

A mixture of tert-butyl4-[4-[(4-chloro-2-fluoro-phenyl)methoxy]thiazol-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate(26 mg, 61.19 μmol) and 2,2,2-trifluoroacetic acid (1.48 g, 12.98 mmol,1 mL) in dichloromethane (3 mL) was stirred for 3 hr at 16° C., untilthe reaction was completed as indicated by LCMS, the reaction mixturewas concentrated in vacuo to give the desired product4-[(4-chloro-2-fluoro-phenyl)methoxy]-2-(1,2,3,6-tetrahydropyridin-4-yl)thiazole(20 mg, crude) as a yellow solid. LCMS: [M+H]⁺=325.0; Retention time (10mM NH₄HCO₃)=1.58 min.

Step 4

A mixture of4-[(4-chloro-2-fluoro-phenyl)methoxy]-2-(1,2,3,6-tetrahydropyridin-4-yl)thiazole(15 mg, 46.18 μmol), tert-butyl2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate(15.55 mg, 46.18 μmol) and N-ethyl-N-isopropyl-propan-2-amine (29.84 mg,230.91 μmol, 40.22 L) in N,N-dimethylformamide (3 mL) was stirred for 4hr at 50° C. in a RBF under N₂, until the reaction was completed asindicated by LCMS, the reaction mixture concentrated in vacuo to yield aresidue which was purified by prep-HPLC to give the desired producttert-butyl2-[[4-[4-[(4-chloro-2-fluoro-phenyl)methoxy]thiazol-2-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate(3 mg, 4.80 μmol, 10.39% yield, 100% purity) as a yellow solid. LCMS:[M+H]⁺=625.3; Retention time (10 mM NH₄HCO₃)=1.84 min.

Step 5

A mixture of tert-butyl2-[[4-[4-[(4-chloro-2-fluoro-phenyl)methoxy]thiazol-2-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate(3 mg, 4.80 μmol) and 2,2,2-trifluoroacetic acid (1.48 g, 12.98 mmol, 1mL) in dichloromethane (4 mL) was stirred for 1 h at 16° C. in a RBFunder N₂, until the reaction was complete as indicated by LCMS, thereaction mixture was concentrated in vacuo to give a residue which waspurified by prep-HPLC to give the desired product2-[[4-[4-[(4-chloro-2-fluoro-phenyl)methoxy]thiazol-2-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylicacid (0.8 mg, 1.41 μmol, 29.3% yield, 100% purity) as a white solid.LCMS: [M+H]⁺=569.2; Retention time (10 mM NH₄HCO₃)=1.46 min; Purity:100% (254 nm).

¹H NMR (400 MHz, CD₃OD) δ 8.20 (s, 1H), 7.97 (dd, J=8.5, 1.2 Hz, 1H),7.65-7.52 (m, 2H), 7.30-7.22 (m, 2H), 6.61-6.60 (brs, 1H), 6.39-6.38(brs, 1H), 5.24 (s, 2H), 4.71-4.63 (m, 3H), 4.43 (s, 2H), 4.15 (d,J=13.6 Hz, 1H), 4.05 (d, J=13.6 Hz, 1H), 3.25-3.24 (m, 2H), 2.86-2.80(m, 2H), 2.80-2.73 (m, 1H), 2.65-2.63 (brs, 2H), 2.52-2.50 (m, 1H).

(S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)thiazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 247)

Prepared in analogous manner as for Compound 250. LCMS: [M+H]⁺=568.9;Retention time (10 mM NH₄HCO₃)=1.41 min.

¹H NMR (400 MHz, CD₃OD) δ 8.37 (d, J=0.9 Hz, 1H), 8.07 (dd, J=8.5, 1.5Hz, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.33-7.23 (m,2H), 6.93 (s, 1H), 6.60 (s, 1H), 5.54 (s, 2H), 5.28-5.14 (m, 1H),5.11-4.90 (m, 2H), 4.79 (dd, J=15.8, 6.9 Hz, 1H), 4.67 (dt, J=13.8, 5.4Hz, 2H), 4.42 (dt, J=9.3, 5.9 Hz, 1H), 4.23 (s, 2H), 3.80 (d, J=5.4 Hz,2H), 3.00-2.72 (m, 3H), 2.51 (dq, J=11.3, 7.4 Hz, 1H).

(S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)oxazol-4-yl)-5,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 248)

Prepared in analogous manner as for Compound 250. LCMS: [M+H]⁺=553.2;Retention time (0.01% TFA)=1.50 min.

¹H NMR (400 MHz, CDCl₃) δ 7.73 (brs, 3H), 7.46 (t, J=8.0 Hz, 1H), 7.16(t, J=9.3 Hz, 3H), 6.39 (s, 1H), 5.44 (s, 2H), 5.15 (s, 1H), 4.59 (d,J=5.6 Hz, 3H), 4.34 (s, 2H), 2.70 (s, 3H), 2.41 (s, 3H), 2.06 (d, J=14.3Hz, 5H).

(S)-2-((4-(2-((4-(cyclopropylethynyl)-2-fluorobenzyl)oxy)thiazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 249)

Prepared in analogous manner as for Compound 250. LCMS: [M+H]⁺=599.0;Retention time (10 mM NH₄HCO₃)=1.68 min.

¹H NMR (400 MHz, DMSO-D6-d6) δ 8.23-8.18 (brs, 1H), 7.80 (dd, J=8.4, 1.4Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.53 (t, J=7.9 Hz, 1H), 7.26 (dd,J=10.8, 1.2 Hz, 1H), 7.22 (dd, J=7.9, 1.4 Hz, 1H), 6.87-6.82 (brs, 1H),6.47-6.42 (m, 1H), 5.46 (s, 2H), 5.09-5.02 (m, 1H), 4.78 (dd, J=15.2,7.2 Hz, 1H), 4.62 (dd, J=15.1, 2.6 Hz, 1H), 4.47 (dd, J=13.7, 7.6 Hz,1H), 4.36 (dt, J=9.0, 5.9 Hz, 1H), 4.04 (d, J=13.4 Hz, 1H), 3.89 (d,J=13.4 Hz, 1H), 3.21-3.11 (m, 2H), 2.73-2.62 (m, 3H), 2.42-3.32 (m, 3H),1.60-1.50 (m, 1H), 0.94-0.87 (m, 2H), 0.77-0.72 (m, 2H).

(S)-2-((4-(2-((5-chloropyridin-2-yl)methoxy)thiazol-4-yl)-3,6-dihydropyridin-(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 250)

Step 1

To a suspension of (5-chloro-2-pyridyl)methanol (100 mg, 696.5 μmol) inTHF (4 mL) was added sodium hydride (33.4 mg, 1.39 mmol) at 0° C. andstirred for 30 min. Then 2,4-dibromothiazole (169.2 mg, 696.5 μmol) wasadded and stirred for 5 h at 0° C. After completion of the reaction asjudged by LCMS, reaction mixture was quenched with ice-cold water (20mL) and extracted with EtOAc (3×20 mL). The organic phase was washedwith brine (50 mL) and dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by flashchromatography (SiO₂, hexane/ethyl acetate 20:1) to afford4-bromo-2-[(5-chloro-2-pyridyl)methoxy]thiazole (78 mg, 232.4 μmol,yield 33.4%), as colorless oil. LCMS: [M+H]+=304.9; Retention time(0.01% TFA)=2.02 min.

Step 2

To a suspension of 4-bromo-2-[(5-chloro-2-pyridyl)methoxy]thiazole (78mg, 255.25 μmol) in 1,4-dioxane (3 mL) was added methyl3-[[(2S)-oxetan-2-yl]methyl]-2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]methyl]benzimidazole-5-carboxylate(119.3 mg, 255.3 μmol), Pd(dppf)Cl₂ (37.35 mg, 51.1 μmol), K₂CO₃ (105.8mg, 765.8 μmol, 46.22 μL) and water (0.3 mL) at 100° C. and stirred for6 h under N₂. After completion of the reaction as judged by LCMS,reaction mixture was quenched with ice-cold water (20 mL) and extractedwith EtOAc (3×20 mL). The organic phase was washed with brine (50 mL)and dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude product was purified by prep-TLC (Dichloromethane/methanol 25:1)to afford methyl(S)-2-((4-(2-((5-chloropyridin-2-yl)methoxy)thiazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(100 mg, 139.3 μmol, 54.6% yield, 78.9% purity) as a yellow oil. LCMS:[M+H]⁺=566.1; Retention time (0.01% TFA)=1.48 min.

Step 3

To a suspension of methyl methyl(S)-2-((4-(2-((5-chloropyridin-2-yl)methoxy)thiazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(100 mg, 176.7 μmol) in MeOH (3 mL) was added sodium hydroxide (80 mg,2.00 mmol, 37.6 L) in water (1 mL) at r.t and stirred for 12 h Aftercompletion of the reaction as judged by LCMS, reaction mixture wasquenched with ice-cold water (10 mL) and extracted with EtOAc (3×10 mL).The organic phase was washed with brine (20 mL) and dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude product waspurified by prep-HPLC to afford(S)-2-((4-(2-((5-chloropyridin-2-yl)methoxy)thiazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (39.1 mg, 70.8 μmol, 40.1% yield) as a yellow solid. LCMS:[M+H]⁺=552.0; Retention time (0.01% TFA)=1.45 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.64 (d, J=2.1 Hz, 1H), 8.25 (t, J=3.2 Hz,1H), 7.99 (dd, J=8.4, 2.5 Hz, 1H), 7.81 (dd, J=8.4, 1.5 Hz, 1H), 7.65(d, J=8.4 Hz, 1H), 7.59 (t, J=8.4 Hz, 1H), 6.86-6.85 (brs, 1H), 6.39 (s,1H), 5.51 (s, 2H), 5.05 (qd, J=7.4, 2.8 Hz, 1H), 4.79 (dd, J=15.2, 7.4Hz, 1H), 4.64 (dd, J=15.2, 2.6 Hz, 1H), 4.47 (dd, J=14.2, 7.0 Hz, 1H),4.36 (dt, J=9.0, 5.9 Hz, 1H), 4.05 (d, J=13.5 Hz, 1H), 3.89 (d, J=13.5Hz, 1H), 3.21-3.11 (m, 2H), 2.66 (dd, J=16.2, 11.1, 7.2 Hz, 3H),2.46-2.31 (m, 3H).

(S)-1-(oxetan-2-ylmethyl)-2-((4-(2-((4-(trifluoromethoxy)benzyl)oxy)thiazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 251)

Prepared in analogous manner as for Compound 250. LCMS: [M+H]⁺=601.0;Retention time (10 mM NH₄HCO₃)=1.63 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.24 (s, 1H), 7.83-7.79 (m, 1H), 7.66-7.61(m, 3H), 7.43-7.38 (m, 2H), 6.85 (s, 1H), 6.48-6.44 (m, 1H), 5.48 (s,2H), 5.10-5.02 (m, 1H), 4.84-4.75 (m, 1H), 4.68-4.61 (m, 1H), 4.51-4.44(m, 1H), 4.40-4.33 (m, 1H), 4.09-3.87 (dd, J=63.2, 13.4 Hz, 2H),3.22-3.15 (m, 2H), 2.75-2.64 (m, 3H), 2.42-2.35 (m, 3H).

(S)-2-((4-(2-((2,4-difluorobenzyl)oxy)thiazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 252)

Prepared in analogous manner as for Compound 250. LCMS: [M+H]⁺=553.0;Retention time (10 mM NH₄HCO₃)=1.54 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.24 (s, 1H), 7.80 (dd, J=1.2 Hz, J=8.4 Hz,1H), 7.70-7.62 (m, 2H), 7.35-7.29 (m, 1H), 7.16-7.11 (m, 1H), 6.84 (s,1H), 6.46 (s, 1H), 5.45 (s, 2H), 5.06-5.04 (m, 1H), 4.81-4.76 (m, 1H),4.66-4.61 (dd, J=2.4 Hz, J=15.2 Hz, 1H), 4.46 (t, J=6 Hz, 1H), 4.39-4.35(m, 1H), 4.05 (d, J=13.6 Hz, 1H), 3.89 (d, J=13.6 Hz, 1H), 3.18 (d,J=9.6 Hz, 2H), 2.72-2.63 (m, 3H), 2.46-2.32 (m, 3H).

(S)-2-((4-(2-((5-bromopyridin-2-yl)methoxy)thiazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 253)

Prepared in analogous manner as for Compound 250. LCMS: [M+H]⁺=596.0;Retention time (10 mM NH₄HCO₃)=1.47 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.72 (d, J=1.9 Hz, 1H), 8.25 (d, J=1.0 Hz,1H), 8.11 (dd, J=8.3, 2.4 Hz, 1H), 7.81 (dd, J=8.4, 1.5 Hz, 1H), 7.64(d, J=8.4 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 6.86 (s, 1H), 6.39 (s, 1H),5.48 (s, 2H), 5.13-4.99 (m, 1H), 4.79 (dd, J=15.2, 7.3 Hz, 1H), 4.64(dd, J=15.2, 2.6 Hz, 1H), 4.46 (dd, J=14.2, 7.1 Hz, 1H), 4.36 (dt,J=8.9, 5.9 Hz, 1H), 4.05 (d, J=13.5 Hz, 1H), 3.89 (d, J=13.5 Hz, 1H),3.24-3.09 (m, 2H), 2.77-2.59 (m, 3H), 2.40 (dd, J=18.2, 9.4 Hz, 3H).

(S)-2-((4-(2-((2-chloro-4-fluorobenzyl)oxy)thiazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 254)

Prepared in analogous manner as for Compound 250. LCMS: [M+H]⁺=569.0;Retention time (10 mM NH₄HCO₃)=1.59 min.

¹H NMR (400 MHz, CD₃OD) δ 8.31 (s, 1H), 8.00-7.97 (m, 1H), 7.69-7.67 (m,1H), 7.64-7.62 (m, 1H), 7.31-7.29 (m, 1H), 7.15-7.10 (m, 1H), 6.67 (s,1H), 6.55-6.52 (m, 1H), 5.54 (s, 2H), 5.28-5.22 (m, 1H), 4.88-4.86 (m,1H), 4.74-4.70 (m, 1H), 4.66-4.60 (m, 1H), 4.50-4.45 (m, 1H), 4.12 (dd,J=13.6 Hz, 2H), 3.28-3.22 (m, 2H), 2.84-2.79 (m, 2H), 2.77-2.73 (m, 1H),2.56-2.48 (m, 3H).

(S)-1-(oxetan-2-ylmethyl)-2-((4-(2-((6-(trifluoromethyl)pyridin-3-yl)methoxy)thiazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 255)

Prepared in analogous manner as for Compound 250. LCMS: [M+H]⁺=586.3;Retention time (10 mM NH₄HCO₃)=1.50 min, Purity: 100% (254 nm).

¹H NMR (400 MHz, DMSO-D6) δ 8.90 (s, 1H), 8.27-8.18 (m, 2H), 7.96 (d,J=8.1 Hz, 1H), 7.80 (dd, J=8.4, 1.5 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H),6.87 (s, 1H), 6.45 (s, 1H), 5.61 (brs, 2H), 5.09-5.01 (m, 1H), 4.79 (dd,J=15.1, 7.2 Hz, 1H), 4.63 (dd, J=15.2, 2.6 Hz, 1H), 4.47 (dd, J=13.6,7.7 Hz, 1H), 4.36 (dt, J=8.9, 5.9 Hz, 1H), 4.05 (d, J=13.5 Hz, 1H), 3.89(d, J=13.5 Hz, 1H), 3.18 (d, J=9.3 Hz, 2H), 2.75-2.60 (m, 3H), 2.43-2.32(m, 3H).

(S)-1-(oxetan-2-ylmethyl)-2-((4-(2-((4-(trifluoromethyl)benzyl)oxy)thiazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 256)

Prepared in analogous manner as for Compound 250. LCMS: [M+H]⁺=585.0;Retention time (10 mM NH₄HCO₃)=1.61 min ¹H NMR (400 MHz, DMSO-D6) δ 8.23(s, 1H), 7.81-7.76 (m, 3H), 7.70 (d, J=8 Hz, 2H), 7.62 (d, J=8.8 Hz,1H), 6.85 (s, 1H), 6.43 (s, 1H), 5.55 (s, 2H), 5.05 (t, J=4.4 Hz, 1H),4.81-4.75 (m, 1H), 4.63 (dd, J=3.2 Hz, J=15.6 Hz, 1H), 4.45 (t, J=5.6Hz, 1H), 4.38-4.33 (m, 1H), 4.05 (d, J=13.6 Hz, 1H), 3.88 (d, J=13.6 Hz,1H), 3.19-3.12 (m, 2H), 2.70-2.63 (m, 3H), 2.43-2.32 (m, 3H).

(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 257)

Step 1

To a mixture of methyl 4-amino-3-[[(2S)-oxetan-2-yl] methylamino]benzoate (100 mg, 423 μmol) in DCM (20 mL) was added slowly2-(4-bromo-2, 5-difluoro-phenyl) acetyl chloride (228 mg, 847 μmol) inDCM (20 mL) at ice-bath, and stirred for 1 h at rt, until the reactionwas complete as indicated by LCMS, the reaction mixture was concentratedin vacuo, purified by prep-TLC (Hexanes/EtOAc=1:2) to give the desiredproduct methyl 4-[[2-(4-bromo-2, 5-difluoro-phenyl) acetyl]amino]-3-[[(2S)-oxetan-2-yl] methylamino] benzoate (71 mg, 151 μmol,35.9% yield) as a pale yellow solid. LCMS: [M+H]⁺=469.0; Retentiontime=1.57 min.

Step 2

A mixture of methyl 4-[[2-(4-bromo-2, 5-difluoro-phenyl) acetyl]amino]-3-[[(2S)-oxetan-2-yl]methylamino] benzoate (71 mg, 151 μmol) inAcOH (5 mL) was stirred for 30 min at 120° C., until the reaction wascomplete as indicated by LCMS, the reaction mixture was concentrated invacuo, purified by silica gel chromatography (Hexanes/EtOAc=20:1) togive the desired product methyl(S)-2-(4-bromo-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(40 mg, 89 μmol, 58.6% yield) as pale yellow solid. LCMS: [M+H]⁺=451.1;Retention time (0.01% TFA)=1.49 min.

Step 3

A mixture of(S)-2-(4-bromo-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(40 mg, 89 μmol), 4, 4, 5, 5-tetramethyl-2-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-1, 3, 2-dioxaborolane (29 mg, 115 μmol),Pd(dppf)Cl₂ (8 mg, 11 μmol) and KOAc (13 mg, 133 μmol) in dioxane (10mL) was stirred for 2 h at 90° C. under Argon, until the reaction wascomplete as indicated by LCMS, the reaction mixture was filtered througha pad of Celite with EtOAc, and the combined organics were concentratedin vacuo to give the desired product methyl(S)-2-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(42 mg, 33.0% yield) as a pale yellow solid. The crude was directly usedin next step without further purification.

LCMS: [M+H]⁺=452.9; Retention time=1.83 min.

Step 4

A mixture of methyl(S)-2-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(42 mg, 84 μmol), 2-bromo-6-[(4-chloro-2-fluoro-phenyl) methoxy]pyridine(32 mg, 101 μmol), Pd(dppf)Cl₂ (6 mg, 8 μmol) and K₂CO₃ (15 mg, 110μmol) in dioxane (5 mL) and H₂O (1 mL) was stirred for 1 h at 90° C.under Argon, until the reaction was complete as indicated by LCMS, thereaction mixture was filtered through a pad of Celite with EtOAc, andthe combined organics were concentrated in vacuo, purified by silica gelchromatography (Hexanes/EtOAc=20:1) to give the desired product methyl(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(12 mg, 20 μmol, 24.0% yield) as pale yellow solid. LCMS: [M+H]⁺=608.0;Retention time=2.28 min.

Step 5

To a mixture of methyl(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(13 mg, 21 μmol) in THF:MeOH:H₂O (3 mL:3 mL:1 mL) was added LiOH (5 mg,107 μmol), and stirred for 1 h at rt, until the reaction was complete asindicated by LCMS, the reaction mixture was concentrated in vacuo,adjusted pH=7 with aqueous acetic acid (50%), purified by prep-HPLC togive the desired product(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (10.1 mg, 17 μmol, 79.5% yield) as a white solid. LCMS:[M+H]⁺=594.1; Retention time=1.44 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.24 (brs, 1H), 7.89 (t, J=7.6, 8 Hz, 1H),7.83 (t, J=6.4, 4.4 Hz, 1H), 7.79 (t, J=7.2, 1.2 Hz, 1H), 7.62-7.58 (m,2H), 7.52-7.48 (m, 2H), 7.41 (dd, J=6.4, 5.2 Hz, 1H), 7.34 (dd, J=6.4,1.6 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 5.50 (s, 2H), 5.08-5.04 (m, 1H),4.78 (dd, J=7.2, 8 Hz, 1H), 4.64 (dd, J=2, 13.2 Hz, 1H), 4.54-4.49 (m,2H), 4.47-4.42 (m, 1H), 4.38-4.33 (m, 1H), 2.74-2.67 (m, 1H), 2.45-2.33(m, 1H).

(S)-2-(2-chloro-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 258)

Prepared in analogous manner as for Compound 257. LCMS: [M+H]⁺=593.1;Retention time=1.55 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.25 (s, 1H), 8.15-8.14 (m, 1H), 8.03-8.00(dd, J=8.1, 1.8 Hz, 1H), 7.88-7.82 (m, 1H), 7.80-7.77 (m, 1H), 7.68-7.55(m, 3H), 7.52-7.48 (dd, J=10.0, 2.0 Hz, 1H), 7.46-7.43 (m, 1H),7.34-7.31 (dd, J=8.2, 1.9 Hz, 1H), 6.91-6.88 (m, 1H), 5.52 (s, 2H),5.10-5.04 (m, 1H), 4.75-4.69 (m, 1H), 4.63-4.56 (m, 2H), 4.52-4.47 (m,2H), 4.40-4.35 (m, 1H), 2.74-2.67 (m, 1H), 2.43-2.39 (m, 1H).

(S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 259)

Prepared in analogous manner as for Compound 257. LCMS: [M+H]⁺=577.0;Retention time=1.54 min.

¹H NMR (400 MHz, MeOD) δ 8.61 (dd, J=23.8, 5.1 Hz, 1H), 8.30 (s, 1H),8.17-7.99 (m, 2H), 7.70 (dd, J=8.5, 4.7 Hz, 1H), 7.62-7.57 (m, 1H),7.34-7.20 (m, 4H), 6.88 (d, J=5.9 Hz, 1H), 5.59 (s, 2H), 5.16-5.11 (m,1H), 4.71-4.62 (m, 2H), 4.60 (d, J=5.2 Hz, 2H), 4.52 (d, J=15.6 Hz, 1H),4.47-4.41 (m, 1H), 2.76 (d, J=8.3 Hz, 1H), 2.49-2.44 (m, 1H).

(S)-2-(4-(6-(4-chloro-2-fluorobenzyloxy)-3,5-difluoropyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 260)

Prepared in analogous manner as for Compound 257. LCMS: [M+H]⁺=612.0;Retention time=1.65 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.22 (d, J=0.9 Hz, 1H), 8.14 (t, J=9.9 Hz,1H), 7.78 (dd, J=8.4, 1.5 Hz, 1H), 7.72 (t, J=8.7 Hz, 2H), 7.62 (t,J=8.2 Hz, 1H), 7.58-7.44 (m, 3H), 7.35 (dd, J=8.2, 1.8 Hz, 1H), 5.57 (s,2H), 5.10-4.98 (m, 1H), 4.72 (dd, J=15.6, 7.1 Hz, 1H), 4.63-4.29 (m,5H), 2.75-2.64 (m, 1H), 2.38 (dt, J=11.1, 7.1 Hz, 1H).

(S)-2-(4-(6-(4-chloro-2-fluorobenzyloxy)-3-fluoropyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 261)

Prepared in analogous manner as for Compound 257. LCMS: [M+H]⁺=594.1;Retention time (10 mM NH₄HCO₃)=1.53 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.20 (s, 1H), 7.80-7.86 (m, 2H), 7.55-7.61(m, 3H), 7.48 (dd, J=2.0 Hz, 10.0 Hz, 1H), 7.32-7.36 (m, 3H), 7.02 (dd,J=3.2 Hz, 9.2 Hz, 1H), 5.38 (s, 2H), 4.97-5.03 (m, 1H), 4.68-4.72 (m,1H), 4.44-4.58 (m, 4H), 4.34-4.39 (m, 1H), 2.66-2.70 (m, 1H), 2.33-2.42(m, 1H).

(S)-2-(4-(6-(4-chloro-2-fluorobenzyloxy)pyridin-2-yl)-2,3-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 262)

Prepared in analogous manner as for Compound 257. LCMS: [M+H]⁺=594.0;Retention time (0.01% TFA)=1.67 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.20 (s, 1H), 7.92-7.86 (m, 1H), 7.82-7.73(m, 2H), 7.61 (t, J=8.2 Hz, 1H), 7.56-7.47 (m, 3H), 7.36-7.26 (m, 2H),6.95 (d, J=8.2 Hz, 1H), 5.48 (s, 2H), 5.12-5.04 (m, 1H), 4.77-4.68 (m,1H), 4.64-4.55 (m, 2H), 4.54-4.46 (m, 2H), 4.40-4.32 (m, 1H), 2.77-2.66(m, 1H), 2.45-2.32 (m, 1H).

(S)-2-(4-(4-(4-cyano-2-fluorobenzyloxy)-5-fluoropyrimidin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 263)

Prepared in analogous manner as for Compound 257. LCMS: [M+H]⁺=587.0;Retention time=1.50 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.79 (d, J=2.8 Hz, 1H), 8.12 (dd, J=8.0 Hz,1.6 Hz, 1H), 8.08-8.02 (m, 2H), 7.99-7.93 (m, 2H), 7.84 (t, J=7.5 Hz,1H), 7.82 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 5.81 (s,2H), 5.18-5.10 (m, 1H), 4.72 (dd, J=15.1, 6.4 Hz, 1H), 4.68-4.54 (m,3H), 4.53-4.49 (m, 1H), 4.38-4.32 (m, 1H), 2.69-2.65 (m, 1H), 2.39-2.31(m, 1H).

(S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 264)

Prepared in analogous manner as for Compound 257. LCMS: [M+H]⁺=585.1;Retention time=1.43 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.24 (s, 1H), 7.94 (d, J=8.7 Hz, 1H),7.87-7.79 (m, 4H), 7.76 (dd, J=13.3, 8.0 Hz, 3H), 7.69 (d, J=8.3, 2.7Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 5.71 (s, 2H), 5.05-4.98 (m, 1H), 4.72(dd, J=15.6, 7.2 Hz, 1H), 4.62-4.47 (m, 3H), 4.44-4.31 (m, 2H),2.74-2.66 (m, 1H), 2.42-2.36 (m, 1H).

(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyrazin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 265)

Prepared in analogous manner as for Compound 257. LCMS: [M+H]⁺=577.7;Retention time (10 mM NH₄HCO₃)=1.55 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.92 (s, 1H), 8.36 (s, 1H), 8.25 (s, 1H),7.98 (dd, J=16.0, 8.0 Hz, 2H), 7.78 (dd, J=8.0, 4.0 Hz, 1H), 7.66 (t,J=8.2 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.55-7.46 (m, 2H), 7.35 (dd,J=8.2, 1.8 Hz, 1H), 5.57 (s, 2H), 5.11-4.99 (m, 1H), 4.72 (d, J=7.0 Hz,1H), 4.65-4.54 (m, 1H), 4.54-4.41 (m, 3H), 4.36 (dd, J=5.9, 3.1 Hz, 1H),2.77-2.63 (m, 1H), 2.44-2.31 (m, 1H).

(S)-2-(4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 266)

Prepared in analogous manner as for Compound 257. LCMS: [M+H]⁺=586.3;Retention time=1.51 min

¹H NMR (400 MHz, DMSO-D6): δ 8.78 (d, J=3.2 Hz, 1H), 8.24 (s, 1H), 8.11(dd, J=1.6, 8.4 Hz, 1H), 8.04 (dd, J=1.6, 11.6 Hz, 1H), 7.97 (dd, J=1.2,10 Hz, 1H), 8.45 (t, J=7.6 Hz, 1H), 7.79-7.76 (m, 2H), 7.57 (t, J=8.8Hz, 1H), 7.48 (t, J=7.6 Hz, 1H), 5.80 (s, 2H), 5.05-5.03 (m, 1H),4.75-4.69 (m, 1H), 4.59 (dd, J=2, 15.2 Hz, 1H), 4.52-4.43 (m, 3H),4.37-4.32 (m, 1H), 2.71-2.67 (m, 1H), 2.39-2.32 (m, 1H).

(S)-2-(4-(6-(2,4-difluorobenzyloxy)-5-fluoropyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 267)

Prepared in analogous manner as for Compound 257. LCMS: [M+H]⁺=579.1;Retention time (10 mM NH₄HCO₃)=1.45 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.05 (d, J=8.4 Hz, 1H), 7.97-7.93 (m, 2H),7.81 (dd, J=8.4 Hz, 10.4 Hz, 1H), 7.70-7.64 (m, 1H), 7.48-7.46 (m, 1H),7.36-7.31 (m, 3H), 7.17-7.12 (m, 1H), 5.55 (s, 2H), 5.15-5.09 (m, 1H),4.73-4.67 (m, 1H), 4.60-4.47 (m, 4H), 4.40-4.35 (m, 1H), 2.72-2.68 (m,1H), 2.47-2.42 (m, 1H).

(S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)-3-fluoropyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 268)

Prepared in analogous manner as for Compound 257. LCMS: [M+H]⁺=585.0;Retention time=1.55 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.20 (s, 1H), 7.93 (d, J=10.2 Hz, 1H), 7.86(dd, J=10.4, 9.0 Hz, 1H), 7.74 (dt, J=15.8, 10.3 Hz, 5H), 7.54 (d, J=8.4Hz, 1H), 7.47 (t, J=7.9 Hz, 1H), 7.02 (dd, J=8.9, 2.6 Hz, 1H), 5.57 (s,2H), 5.05 (d, J=4.6 Hz, 1H), 4.71 (dd, J=15.5, 7.0 Hz, 1H), 4.61-4.55(m, 1H), 4.54-4.30 (m, 4H), 2.75-2.65 (m, 1H), 2.42-2.34 (m, 1H).

(S)-2-(4-(6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 269)

Prepared in analogous manner as for Compound 257. LCMS: [M+H]⁺=576.9;Retention time=1.52 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.63-8.62 (m 1H), 8.24 (s, 1H), 7.97-7.87(m, 2H), 7.79-7.77 (m, 1H), 7.66-7.62 (m, 1H), 7.59-7.51 (m, 3H),7.38-7.34 (m, 1H), 7.02 (d, J=8.2 Hz, 1H), 5.54 (s, 2H), 5.09-5.06 (m,1H), 4.77-4.71 (m, 1H), 4.63-4.58 (m, 1H), 4.53-4.44 (m, 3H), 4.40-4.33(m, 1H), 2.73-2.67 (m, 1H), 2.42-2.34 (m, 1H).

(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-methylbenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 270)

Prepared in analogous manner as for Compound 257. LCMS: [M+H]⁺=572.0;Retention time=1.65 min.

¹H NMR (400 MHz, DMSO-D6): δ 8.22 (brs, 1H), 7.83-7.82 (m, 2H), 7.62 (d,J=8.4 Hz, 1H), 7.55 (t, J=8.4 Hz, 1H), 7.47 (dd, J=2 Hz, J=8 Hz, 1H),7.36 (d, J=8 Hz, 1H), 7.31 (dd, J=8 Hz, J=6.4 Hz, 1H), 7.24-7.20 (m,2H), 7.14 (d, J=8 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 5.39 (s, 2H),4.966-4.93 (m, 1H), 4.69-4.63 (m, 1H), 4.55-4.44 (m, 2H), 4.40-4.33 (m,3H), 2.67-2.63 (m, 1H), 2.39-2.29 (m, 4H).

(S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 271)

Prepared in analogous manner as for Compound 257. LCMS: [M+H]⁺=585.1;Retention time=1.36 min.

¹H NMR (400 MHz, DMSO-D6-d6) δ 8.24 (brs, 1H), 7.93-7.87 (m, 2H),7.79-7.71 (m, 4H), 7.59 (d, J=8.4 Hz, 1H), 7.53 (dd, J=1.2, 6.4 Hz, 1H),7.40 (dd, J=6.4, 5.2 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 5.59 (s, 2H), 5.08(qd, J=2.8, 7.8 Hz, 1H), 4.77 (dd, J=7.2, 8.4 Hz, 1H), 4.63 (dd, J=2.4,13.2 Hz, 1H), 4.54-4.49 (m, 2H), 4.46 (d, J=6 Hz, 1H), 4.36-4.33 (m,1H), 2.70-2.67 (m, 1H), 2.37-2.32 (m, 1H).

(S)-2-(4-(4-((5-chloro-3-fluoropyridin-2-yl)methoxy)-5-fluoropyrimidin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 272)

Prepared in analogous manner as for Compound 257. LCMS: [M+H]⁺=614.0;Retention time=1.48 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.83 (d, J=2.9 Hz, 1H), 8.54 (d, J=1.4 Hz,1H), 8.27-8.15 (m, 2H), 7.78 (td, J=8.8, 3.9 Hz, 2H), 7.59 (d, J=8.4 Hz,1H), 7.37 (dd, J=11.1, 6.0 Hz, 1H), 5.78 (d, J=1.6 Hz, 2H), 5.13-5.02(m, 1H), 4.74 (dd, J=15.5, 7.0 Hz, 1H), 4.64-4.58 (m, 1H), 4.56-4.41 (m,3H), 4.35 (dt, J=9.0, 5.9 Hz, 1H), 2.75-2.65 (m, 1H), 2.38 (dt, J=11.3,7.1 Hz, 1H).

(S)-2-(4-(4-((5-chloro-3-fluoropyridin-2-yl)methoxy)-5-fluoropyrimidin-2-yl)-2,5-difluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 273)

Prepared in analogous manner as for Compound 257. LCMS: [M+H]⁺=615.0;Retention time=1.37 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.83 (d, J=2.9 Hz, 1H), 8.54 (d, J=1.3 Hz,1H), 8.20 (dd, J=9.7, 2.0 Hz, 1H), 8.04 (d, J=8.2 Hz, 1H), 7.94 (d,J=8.2 Hz, 1H), 7.78 (dd, J=10.2, 6.3 Hz, 1H), 7.40 (dd, J=11.0, 6.0 Hz,1H), 5.77 (d, J=1.6 Hz, 2H), 5.18-5.12 (m, 1H), 4.74 (dd, J=15.2, 6.2Hz, 1H), 4.63 (dd, J=10.3, 6.8 Hz, 2H), 4.56-4.48 (m, 2H), 4.37-4.31 (m,1H), 2.74-2.68 (m, 1H), 2.45-2.40 (m, 1H).

(S)-2-(4-(6-((2,4-difluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 274)

Prepared in analogous manner as for Compound 257. LCMS: [M+H]⁺=560.0;Retention time=1.59 min.

¹H NMR (400 MHz, DMSO-D6-d6) δ 8.23 (brs, 1H), 7.94 (t, J=10, 6.4 Hz,2H), 7.85 (t, J=8, 8 Hz, 1H), 7.79 (dd, J=1.2, 7.2 Hz, 1H), 7.68 (q,J=8.8, 8 Hz, 2H), 7.58 (d, J=8.4 Hz, 1H), 7.45 (t, J=7.6, 8.4 Hz, 1H),7.33 (dt, J=2.4, 8 Hz, 1H), 7.14 (dt, J=2.4, 6.4 Hz, 1H), 6.87 (d, J=8Hz, 1H), 5.50 (s, 2H), 5.06-5.02 (m, 1H), 4.75 (dd, J=7.2, 8.4 Hz, 1H),4.60 (dd, J=2.4, 13.6 Hz, 1H), 4.54-4.48 (m, 2H), 4.46-4.40 (m, 1H),4.38-4.32 (m, 1H), 2.74-2.67 (m, 1H), 2.42-2.33 (m, 1H).

(S)-2-(4-(4-((5-cyanopyridin-2-yl)methoxy)-5-fluoropyrimidin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 275)

Prepared in analogous manner as for Compound 257. LCMS: [M+H]⁺=587.2;Retention time=1.41 min.

¹H NMR (400 MHz, DMSO-D6) δ 9.03 (d, J=1.4 Hz, 1H), 8.85 (d, J=2.8 Hz,1H), 8.36 (dd, J=8.2, 2.1 Hz, 1H), 8.24 (s, 1H), 7.83-7.65 (m, 3H), 7.58(d, J=8.4 Hz, 1H), 7.36 (dd, J=11.1, 6.1 Hz, 1H), 5.79 (s, 2H), 5.06 (d,J=7.0 Hz, 1H), 4.81-4.68 (m, 1H), 4.51 (ddd, J=34.3, 30.6, 14.9 Hz, 4H),4.34 (dd, J=6.0, 3.0 Hz, 1H), 2.69 (d, J=8.3 Hz, 1H), 2.38 (s, 1H).

(S)-2-(4-(6-((5-chloro-3-fluoropyridin-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 276)

Step 1

To a suspension of (5-chloro-3-fluoro-2-pyridyl)methanol (100 mg, 619μmol) and 2-bromo-6-fluoro-pyridine (114.4 mg, 650 μmol) in THF (5 mL)was added slowly t-BuOK (76.4 mg, 681 μmol) at 0° C. and stirred for 2 hunder N₂. After completion of the reaction as judged by LCMS, reactionmixture was quenched with ice-cold water (20 mL) and extracted withEtOAc (3×40 mL). The organic phase was washed with brine (50 mL) anddried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude product was purified by flash chromatography (SiO₂, hexane/ethylacetate 10:1) to afford2-[(6-bromo-2-pyridyl)oxymethyl]-5-chloro-3-fluoro-pyridine (115 mg, 362μmol) as a white solid. LCMS: [M+H]⁺=317.0; Retention time (0.01%TFA)=2.12 min.

Step 2

A mixture of methyl 2-(4-bromo-2,5-difluoro-phenyl)acetate (400 mg, 1.51mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(459.9 mg, 1.81 mmol), KOAc (296.22 mg, 3.02 mmol) and Pd(dppf)Cl₂(110.4 mg, 151 μmol) in dioxane (8 mL) was stirred for 2 h at 95° C.under N₂, until the reaction was complete as indicated by LCMS, thereaction mixture was used in the next run without further purification.

LCMS: [M+H]⁺=231.1; Retention time (0.01% TFA)=1.53 min.

Step 3

A mixture of 2-[(6-bromo-2-pyridyl)oxymethyl]-5-chloro-3-fluoro-pyridine(110 mg, 346 μmol), methyl2-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate(129.7 mg, 416 μmol), Pd(dppf)Cl₂ (50.7 mg, 69 μmol) and Cs₂CO₃ (225.74mg, 693 μmol) in dioxane (8 mL) and water (1.5 mL) was stirred for 2 hat 100° C. under N₂, until the reaction was complete as indicated byLCMS, the reaction mixture was filtered through a pad of Celite withEtOAc, and the combined organics were concentrated in vacuo, purified bysilica gel chromatography (Hexanes/EtOAc=10:1) to give the desiredproduct methyl2-[4-[6-[(5-chloro-3-fluoro-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]acetate(110 mg, 260 μmol) as white solid.

LCMS: [M+H]⁺=423.0; Retention time (0.01% TFA)=2.22 min.

Step 4

A mixture of methyl2-[4-[6-[(5-chloro-3-fluoro-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]acetate(100 mg, 237 μmol), LiOH (16.99 mg, 710 μmol) and water (0.5 mL) inmethanol (3 mL) was stirred for 12 h at 20° C. under N₂, until thereaction was complete as indicated by LCMS, HOAc was added to quench thereaction, and the combined organics were concentrated in vacuo, purifiedby HPLC to give the desired product2-[4-[6-[(5-chloro-3-fluoro-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]aceticacid (90 mg, 220 μmol, 93.1% yield) as white solid. LCMS: [M+H]⁺=409.1;Retention time (0.01% TFA)=1.99 min.

Step 5

A mixture of2-[4-[6-[(5-chloro-3-fluoro-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]aceticacid (90 mg, 220 μmol), methyl5-amino-6-[[(2S)-oxetan-2-yl]methylamino]pyridine-2-carboxylate (94.03mg, 396 μmol), HATU (125.6 mg, 330 μmol) and DIEA (85.4 mg, 661 μmol) inDCM (8 mL) was stirred for 2 h at 20° C. under N₂, until the reactionwas complete as indicated by LCMS, water was added to quench thereaction, and the combined organics were concentrated in vacuo, purifiedby silica gel chromatography (Hexanes/EtOAc=1:1) to give the desiredproduct methyl5-[[2-[4-[6-[(5-chloro-3-fluoro-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]acetyl]amino]-6-[[(2S)-oxetan-2-yl]methylamino]pyridine-2-carboxylate(120 mg, 191 μmol, 86.8% yield) as pale yellow solid. LCMS:[M+H]⁺=628.1; Retention time (0.01% TFA)=1.77 min.

Step 6

A mixture of methyl5-[[2-[4-[6-[(5-chloro-3-fluoro-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]acetyl]amino]-6-[[(2S)-oxetan-2-yl]methylamino]pyridine-2-carboxylate(90 mg, 143 μmol) and HOAc (20 drops) in toluene (10 mL) was stirred for2 h at 60° C. under N₂. Water was added to quench the reaction. Thereaction mixture was extracted with EtOAc (3×20 mL). The organic phasewas washed with brine (50 mL) and dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The crude product was purified by flashchromatography (SiO₂, dichloromethane/methanol 15:1) to afford methyl2-[[4-[6-[(5-chloro-3-fluoro-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate(74 mg, 121 μmol, 84.7% yield) as a yellow oil. LCMS: [M+H]⁺=610.2;Retention time (0.01% TFA)=2.07 min.

Step 7

A mixture of methyl2-[[4-[6-[(5-chloro-3-fluoro-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate(40 mg, 66 μmol), LiOH (4.7 mg, 197 μmol) and water (0.5 mL) in methanol(3 mL) was stirred for 3 h at 20° C. under N₂, until the reaction wascomplete as indicated by LCMS, HOAc was added to quench the reaction,and the combined organics were concentrated in vacuo, purified by HPLCto give the desired product2-[[4-[6-[(5-chloro-3-fluoro-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylicacid (22 mg, 37 μmol, 56.3% yield) as white solid. LCMS: [M+H]⁺=596.0;Retention time (0.01% TFA)=1.90 min.

¹H NMR (400 MHz, DMSO-D6) δ8.53 (d, J=1.2 Hz, 1H), 8.18-8.15 (m, 1H),8.08 (d, J=8.4 Hz, 1H), 7.97 (dd, J=8.0 Hz, 1H), 7.90-7.86 (m, 1H), 7.72(dd, J=6.4 Hz, 10.4 Hz, 1H), 7.52 (d, J=6.0 Hz, 1H), 7.41 (dd, J=6.0 Hz,11.6 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 5.59 (d, J=1.6 Hz, 2H), 5.17-5.15(m, 1H), 4.79-4.73 (m, 1H), 4.65-4.61 (m, 2H), 4.55-4.49 (m, 2H),4.39-4.33 (m, 1H), 2.76-2.71 (m, 1H), 2.47-2.42 (m, 1H).

(S)-2-(4-(6-(2,4-difluorobenzyloxy)-5-fluoropyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 277)

Prepared in analogous manner as for Compound 276. LCMS: [M+H]⁺=579.1;Retention time (10 mM NH₄HCO₃)=1.46 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.02-7.80 (m, 5H), 7.71-7.65 (m, 2H),7.48-7.44 (m, 1H), 7.36-7.31 (m, 1H), 7.17-7.12 (m, 1H), 5.60 (s, 2H),5.17-5.11 (m, 1H), 4.75-4.69 (m, 1H), 4.64-4.59 (m, 2H), 4.53-4.49 (m,2H), 4.38-4.33 (m, 1H), 2.75-2.67 (m, 1H), 2.48-2.41 (m, 1H).

(S)-2-(4-(6-((5-cyano-3-fluoropyridin-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 278)

Prepared in analogous manner as for Compound 276. LCMS: [M+H]⁺=587.1;Retention time (10 mM NH₄HCO₃)=1.35 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.89 (s, 1H), 8.48 (dd, J=1.6 Hz, 9.6 Hz,1H), 8.07 (d, J=8.4 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.90-7.87 (m, 1H),7.61-7.57 (m, 1H), 7.51 (d, J=6.0 Hz, 1H), 7.39 (dd, J=6.4 Hz, 11.2 Hz,1H), 6.99 (d, J=8.4 Hz, 1H), 5.69 (d, J=1.2 Hz, 2H), 5.19-5.13 (m, 1H),4.78-4.73 (m, 1H), 4.65-4.60 (m, 2H), 4.54-4.48 (m, 2H), 4.38-4.33 (m,1H), 2.75-2.69 (m, 1H), 2.47-2.40 (m, 1H).

(S)-2-(4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 279)

Step 1

A mixture of 6-(hydroxymethyl)pyridine-3-carbonitrile (33 mg, 246 μmol),2-bromo-6-fluoro-pyridine (43.3 mg, 246 μmol) and sodium hydride (5.7mg, 246 μmol) in THF (3 mL) was stirred for 2 h at 20° C. under N₂,until the reaction was complete as indicated by LCMS, the reactionmixture was filtered through a pad of Celite with EtOAc, and thecombined organics were concentrated in vacuum, purified by silica gelchromatography (Hexanes/EtOAc=20:1) to give the desired product6-[(6-bromo-2-pyridyl)oxymethyl]pyridine-3-carbonitrile (30 mg, 103μmol, 42.0% yield) as pale yellow solid. LCMS: [M+H]⁺=290; Retentiontime (0.01% TFA)=1.86 min.

Step 2

A mixture of tert-butyl5-amino-6-[[(2S)-oxetan-2-yl]methylamino]pyridine-2-carboxylate (1.39 g,4.98 mmol) 2-(4-bromo-2, 5-difluoro-phenyl)acetic acid (1.25 g, 4.98mmol) N-ethyl-N-isopropyl-propan-2-amine (643.6 mg, 4.98 mmol) and[dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium,hexafluorophosphate (1.89 g, 4.98 mmol) in DMF (20 mL) was stirred for 1h at 20° C. under N2, until the reaction was complete as indicated byLCMS, the reaction mixture was poured into water and extracted withEtOAc, and the combined organics were concentrated in vacuum, purifiedby silica gel chromatography (Hexanes/EtOAc=2:1) to give the desiredproduct tert-butyl5-[[2-(4-bromo-2,5-difluoro-phenyl)acetyl]amino]-6-[[(2S)-oxetan-2-yl]methylamino]pyridine-2-carboxylate(1.0 g, 1.95 mmol, 39.2% yield) as pale yellow solid. LCMS: [M+H]⁺=512;Retention time=1.92 min.

Step 3

A mixture of tert-butyl5-[[2-(4-bromo-2,5-difluoro-phenyl)acetyl]amino]-6-[[(2S)-oxetan-2-yl]methylamino]pyridine-2-carboxylate(1.0 g, 1.95 mmol) in toluene (10 mL) was stirred for 2 h at 120° C.under N2, until the reaction was complete as indicated by LCMS, thereaction mixture was filtered through a pad of Celite with EtOAc, andthe combined organics were concentrated in vacuum, purified by silicagel chromatography (Hexanes/EtOAc=2:1) to give the desired producttert-butyl2-[(4-bromo-2,5-difluoro-phenyl)methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate(430 mg, 870 μmol, 44.6% yield) as pale yellow solid. LCMS: [M+H]+=494;Retention time (0.01% TFA)=2.02 min.

Step 4

A mixture of tert-butyl2-[(4-bromo-2,5-difluoro-phenyl)methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate(180 mg, 364 μmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(184.93 mg, 728 μmol), and potassium acetate (143.0 mg, 1.46 mmol) indioxane (20 mL) was stirred for 16 h at 90° C. under N₂, until thereaction was complete as indicated by LCMS, the reaction mixture wasfiltered through a pad of Celite with EtOAc, used for next step,directly.

Step 5

A mixture of 6-[(6-bromo-2-pyridyl)oxymethyl]pyridine-3-carbonitrile (60mg, 207 μmol), tert-butyl2-[[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate(112.0 mg, 207 μmol) and sodium hydrogen carbonate (86.87 mg, 1.03 mmol)in was stirred for 16 h at 110° C. under N₂, until the reaction wascomplete as indicated by LCMS, the reaction mixture was poured intowater and extracted with EtOAc, and the combined organics wereconcentrated in vacuum, purified by silica gel chromatography(Hexanes/EtOAc=5:1) to give the desired product tert-butyl2-[[4-[6-[(5-cyano-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate(80 mg, 61.9% yield) as pale yellow oil. LCMS: [M+H]⁺=625; Retentiontime=1.77 min.

Step 6

A mixture of tert-butyl2-[[4-[6-[(5-cyano-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate(80 mg, 128 μmol), 2,2,2-trifluoroacetic acid (23.68 g, 207.68 mmol,16.00 mL) in CH₂Cl₂ (2 mL) was stirred for 1 h at 30° C. under N2, untilthe reaction was complete as indicated by LCMS, the reaction mixturewere concentrated in vacuum and further purified with PREP-HPLC to givethe desired product2-[[4-[6-[(5-cyano-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylicacid (38.3 mg, 51.0% yield) as pale yellow solid. LCMS: [M+H]⁺=569.2;Retention time=1.42 min.

¹H NMR (400 MHz, DMSO-D6) δ 9.03 (d, J=1.4 Hz, 1H), 8.33 (dd, J=8.2, 2.1Hz, 1H), 8.08 (d, J=8.2 Hz, 1H), 8.02-7.85 (m, 2H), 7.68 (d, J=8.2 Hz,1H), 7.54 (dd, J=10.9, 6.7 Hz, 2H), 7.39 (dd, J=11.5, 6.0 Hz, 1H), 7.06(d, J=8.3 Hz, 1H), 5.64 (s, 2H), 5.15 (dd, J=7.1, 3.3 Hz, 1H), 4.75 (dd,J=15.1, 6.4 Hz, 1H), 4.68-4.56 (m, 2H), 4.50 (dd, J=15.5, 5.9 Hz, 2H),4.35 (dd, J=6.0, 2.9 Hz, 1H), 2.73 (d, J=3.3 Hz, 1H), 2.45 (d, J=9.0 Hz,1H).

(S)-2-(4-(4-((5-cyanopyridin-2-yl)methoxy)-5-fluoropyrimidin-2-yl)-2,5-difluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 280)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=588.0;Retention time=1.17 min.

¹H NMR (400 MHz, DMSO-D6) δ 9.04 (d, J=1.4 Hz, 1H), 8.86 (d, J=2.8 Hz,1H), 8.37 (dd, J=8.2, 2.1 Hz, 1H), 8.03 (d, J=8.2 Hz, 1H), 7.94 (d,J=8.2 Hz, 1H), 7.84-7.63 (m, 2H), 7.39 (dd, J=11.1, 6.1 Hz, 1H), 5.80(s, 2H), 5.15 (s, 1H), 4.81-4.41 (m, 6H), 4.41-4.23 (m, 1H), 2.70 (dd,J=16.4, 8.3 Hz, 2H).

2-[[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 281)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=577.9;Retention time (10 mM NH₄HCO₃)=2.94 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.06 (d, J=8.2 Hz, 1H), 7.97 (d, J=8.2 Hz,1H), 7.91 (dd, J=9.1, 5.2 Hz, 2H), 7.84 (t, J=7.8 Hz, 1H), 7.66 (d,J=7.4 Hz, 1H), 7.62 (t, J=8.2 Hz, 1H), 7.54-7.42 (m, 2H), 7.33 (d, J=8.2Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 5.52 (s, 2H), 5.15 (s, 1H), 4.73 (dd,J=15.1, 6.2 Hz, 1H), 4.63 (dd, J=10.3, 6.8 Hz, 2H), 4.51 (dd, J=15.3,9.1 Hz, 2H), 4.36 (dt, J=12.0, 5.9 Hz, 1H), 2.71 (dd, J=17.0, 9.0 Hz,1H), 2.42 (d, J=18.0 Hz, 1H).

(S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 282)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=568.2;Retention time=1.32 min.

¹H NMR (400 MHz, DMSO-D6) δ 7.99 (d, J=8.4 Hz, 1H), 7.96-7.90 (m, 4.0Hz, 2H), 7.90-7.84 (m, J=7.8 Hz, 3H), 7.79-7.71 (m, 2H), 7.67 (d, J=7.4Hz, 1H), 7.44 (t, J=8.1 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 5.62 (s, 2H),5.14 (s, 1H), 4.71 (dd, J=15.3, 6.5 Hz, 1H), 4.60 (d, J=17.0 Hz, 2H),4.54-4.45 (m, 2H), 4.40-4.31 (m, 1H), 2.76-2.68 (m, 1H), 2.43-2.34 (m,1H).

(S)-2-(4-(6-(4-chloro-2-fluorobenzyloxy)-5-fluoropyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 283)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=595.2;Retention time=1.42 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.02 (d, J=8.0 Hz, 1H), 7.94 (d, J=8.4 Hz,1H), 7.91-7.79 (m, 3H), 7.69 (dd, J=8.4, 2.8 Hz, 1H), 7.64 (t, J=8.2 Hz,1H), 7.52 (dd, J=10.0, 2.0 Hz, 1H), 7.45 (t, J=8.1 Hz, 1H), 7.36-7.34(m, 1H), 5.61 (s, 2H), 5.18-5.10 (m, 1H), 4.72 (dd, J=15.0, 6.4 Hz, 1H),4.65-4.61 (m, 1H), 4.60-4.57 (m, 1H), 4.54-4.47 (m, 2H), 4.39-4.32 (m,1H), 2.69-2.66 (m, 1H), 2.34-2.32 (m, 1H).

(S)-2-(4-(6-(4-cyano-2-fluorobenzyloxy)-5-fluoropyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 284)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=586.0;Retention time=1.51 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.04 (d, J=8.0 Hz, 1H), 7.97-7.92 (m, 2H),7.87-7.82 (m, 3H), 7.80-7.73 (m, 2H), 7.70 (dd, J=8.4, 2.8 Hz, 1H), 7.45(t, J=8.0 Hz, 1H), 5.71 (s, 2H), 5.18-5.11 (m, 1H), 4.73 (dd, J=15.2,6.4 Hz, 1H), 4.65-4.61 (m, 1H), 4.60-4.57 (m, 1H), 4.54-4.46 (m, 2H),4.36 (dt, J=9.0, 6.0 Hz, 1H), 2.72-2.66 (m, 1H), 2.40-2.30 (m, 1H).

(S)-2-(4-(4-((2,4-difluorobenzyl)oxy)-5-fluoropyrimidin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 285)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=580.0;Retention time=1.53 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.82-8.76 (m, 1H), 8.19-8.15 (m, 1H),8.13-8.03 (m, 2H), 7.99-7.94 (m, 1H), 7.78-7.70 (m, 1H), 7.56-7.50 (m,1H), 7.41-7.32 (m, 1H), 7.22-7.14 (m, 1H), 5.72 (s, 2H), 5.19-5.11 (m,1H), 4.77-4.49 (m, 5H), 4.39-4.33 (m, 1H), 2.75-2.67 (m, 1H), 2.47-2.40(m, 1H).

(S)-2-(4-(6-((2,4-difluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 286)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=561.0;Retention time=1.57 min.

¹H NMR (400 MHz, DMSO-D6) δ 7.96-7.89 (m, 4H), 7.88-7.82 (m, 1H),7.70-7.62 (m, 2H), 7.48-7.42 (m, 1H), 7.35-7.28 (m, 1H), 7.17-7.08 (m,1H), 6.90-6.85 (m, 1H), 5.51 (s, 2H), 5.18-5.10 (m, 1H), 4.74-4.67 (m,1H), 4.62-4.47 (m, 4H), 4.39-4.33 (m, 1H), 2.76-2.65 (m, 1H), 2.45-2.40(m, 1H).

(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 287)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=576.3;Retention time=2.13 min.

¹H NMR (400 MHz, DMSO-D6) δ 7.95-7.89 (m, 2H), 7.65-7.61 (m, 2H),7.56-7.54 (m, 2H) 7.42-7.31 (m, 5H), 7.06 (d, 1H), 5.23 (s, 2H), 5.00(m, 1H), 4.67-4.66 (m, 1H), 4.57-4.55 (m, 2H), 4.47-4.43 (m, 2H), 4.34(m, 1H), 2.51 (m, 1H), 2.32 (m, 1H)

(S)-2-(4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 288)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=550.7;Retention time=1.98 min.

¹H NMR (400 MHz, DMSO-D6) δ 9.03 (s, 1H), 8.32 (d, 1H), 7.78 (d, 1H),7.77 (d, 1H), 7.76 (d, 1H), 7.64-7.63 (m, 4H), 7.39 (t, 1H), 7.00 (d,1H), 5.64 (s, 2H), 4.51 (m, 1H), 4.46-4.341 (m, 4H), 4.31 (m, 1H),2.71-2.67 (m, 1H), 2.45-2.43 (m, 1H)

(S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 289)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=586.2;Retention time (0.01% TFA)=1.85 min.

¹H NMR (400 MHz, CDCl₃) δ 8.25-8.22 (m, 2H), 7.93-7.87 (m, 1H),7.73-7.67 (m, 1H), 7.50-7.37 (m, 4H), 7.21-7.16 (m, 1H), 7.12-7.08 (m,1H), 5.64 (s, 2H), 5.25-5.19 (m, 1H), 4.71-4.60 (m, 3H), 4.57-4.49 (m,1H), 4.48-4.37 (m, 2H), 2.82-2.75 (m, 1H), 2.46-2.37 (m, 1H).

(S)-2-(4-(6-((2,4-difluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 290)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=561.0;Retention time=1.57 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.15-8.09 (d, J=8.2 Hz, 1H), 8.02-7.95 (m,2H), 7.87-7.81 (m, 1H), 7.69-7.60 (dd, J=15.3, 8.5 Hz, 1H), 7.47-7.43(m, 1H), 7.37-7.27 (m, 3H), 7.15-7.09 (m, 1H), 6.91-6.87 (d, J=8.2 Hz,1H), 5.46 (s, 2H), 5.17-5.09 (m, 1H), 4.76-4.68 (m, 1H), 4.65-4.46 (m,4H), 4.42-4.35 (m, 1H), 2.76-2.64 (m, 1H), 2.47-2.41 (m, 1H).

(S)-2-(4-(2-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidin-4-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 291)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=587.0;Retention time=1.43 min.

¹H NMR (400 MHz, DMSO-D6): δ 8.84 (d, J=3.2 Hz, 1H), 8.04 (d, J=4 Hz,1H), 7.94 (d, J=8.4 Hz, 2H), 7.87 (t, J=8 Hz, 2H), 7.80-7.74 (m, 2H),7.58 (t, J=8 Hz, 1H), 5.60 (s, 2H), 5.16-5.14 (m, 1H), 4.76-4.69 (m,1H), 4.64 (t, J=4 Hz, 2H, 1H), 4.60 (d, J=6.4 Hz, 1H), 4.54-4.47 (m,1H), 4.37-4.32 (m, 1H), 2.74-2.67 (m, 1H), 2.46-2.41 (m, 2H).

(S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 292)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=586.2;Retention time=1.57 min.

¹H NMR (400 MHz, CD₃OD) δ 8.20-8.16 (m, 1H), 8.12-8.08 (m, 1H),7.90-7.87 (m, 1H), 7.86-7.77 (m, 2H), 7.70-7.66 (m, 1H), 7.65-7.60 (m,2H), 7.30-7.24 (m, 1H), 7.00-6.96 (m, 1H), 5.70 (s, 2H), 5.36-5.34 (m,1H), 4.90-4.86 (m, 1H), 4.82-4.79 (m, 1H), 4.73-4.65 (m, 3H), 4.53-4.48(m, 1H), 2.93-2.93 (m, 1H), 2.61-2.56 (m, 1H).

(S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 293)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=568.0;Retention time=1.50 min.

¹H NMR (400 MHz, DMSO-D6): δ 8.76 (d, J=8.4 Hz, 1H), 7.95-7.84 (m, 4H),7.77-7.71 (m, 2H), 7.46 (dd, J=1.6 Hz, J=7.6 Hz, 1H), 7.30 (t, J=11.2Hz, 2H), 6.94 (d, J=8 Hz, 1H), 5.56 (s, 2H), 5.12-5.09 (m, 1H),4.70-4.65 (m, 1H), 4.58-4.46 (m, 4H), 4.38-4.33 (m, 1H), 2.70-2.66 (m,1H), 2.47-2.40 (m, 1H).

(S)-2-(4-(4-((5-chloro-3-fluoropyridin-2-yl)methoxy)-5-fluoropyrimidin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 294)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=597.1;Retention time=1.28 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.77 (d, J=2.8 Hz, 1H), 8.56 (d, J=1.4 Hz,1H), 8.22 (dd, J=9.7, 1.9 Hz, 1H), 8.10-7.90 (m, 4H), 7.49 (t, J=7.9 Hz,1H), 5.82 (d, J=1.4 Hz, 2H), 5.14 (d, J=7.1 Hz, 1H), 4.78-4.45 (m, 5H),4.35 (dt, J=9.0, 6.0 Hz, 1H), 2.70 (dd, J=17.0, 8.8 Hz, 1H), 2.44 (d,J=8.8 Hz, 1H).

(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2-methylbenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 295)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=572.1;Retention time=1.52 min.

¹H NMR (400 MHz, DMSO-D6): δ 8.22 (brs, 1H), 7.90 (brs, 1H), 7.84-7.76(m, 3H), 7.62-7.56 (m, 3H), 7.50 (dd, J=2 Hz, J=10 Hz, 1H), 7.32 (dd,J=1.6 Hz, J=8.4H z, 1H), 7.16 (d, J=8 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H),5.51 (s, 2H), 5.03-5.00 (m, 1H), 4.69-4.63 (m, 1H), 4.56-4.46 (m, 2H),4.43-4.38 (m, 2H), 4.37-4.35 (m, 1H), 2.69-2.65 (m, 1H), 2.42-2.34 (m,4H).

(S)-2-(4-(6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 296)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=578.2;Retention time=1.32 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.63 (d, J=2.4 Hz, 1H), 8.09 (d, J=8.2 Hz,1H), 7.98-7.94 (m, 2H), 7.91-7.87 (m, 1H), 7.67-7.62 (m, 1H), 7.55-7.51(m, 2H), 7.42-7.37 (m, 1H), 7.02 (d, J=8.3 Hz, 1H), 5.54 (s, 2H),5.18-5.14 (m, 1H), 4.78-4.72 (m, 1H), 4.65-4.60 (m, 2H), 4.53-4.48 (m,2H), 4.38-4.32 (m, 1H), 2.76-2.70 (m, 1H), 2.46-2.43 (m, 1H).

(S)-2-(4-(6-((3,5-difluoropyridin-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 297)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=580.0;Retention time=1.48 min.

¹H NMR (400 MHz, DMSO-D6): δ 8.52 (d, J=2.4 Hz, 1H), 8.08-7.84 (m, 4H),7.79-7.75 (m, 1H), 7.52-7.49 (m, 1H), 7.42-7.38 (m, 1H), 6.95-6.92 (m,1H), 5.58 (d, J=1.6 Hz, 2H), 5.18-4.90 (m, 1H), 4.78-4.32 (m, 5H),2.74-2.66 (m, 1H), 2.46-2.39 (m, 2H).

(S)-2-(2,5-difluoro-4-(6-((5-fluoropyridin-2-yl)methoxy)pyridin-2-yl)benzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 298)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=562.0;Retention time=1.40 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.58 (d, J=2.9 Hz, 1H), 8.06 (d, J=8.2 Hz,1H), 7.96 (d, J=8.2 Hz, 1H), 7.92-7.86 (m, 1H), 7.76 (td, J=8.8, 3.0 Hz,1H), 7.69 (dd, J=10.5, 6.5 Hz, 1H), 7.59 (dd, J=8.7, 4.5 Hz, 1H), 7.51(d, J=6.2 Hz, 1H), 7.40 (dd, J=11.5, 6.1 Hz, 1H), 7.00 (d, J=8.2 Hz,1H), 5.53 (s, 2H), 5.19-5.11 (m, 1H), 4.75 (dd, J=15.1, 6.3 Hz, 1H),4.66-4.58 (m, 2H), 4.50 (dd, J=15.4, 6.9 Hz, 2H), 4.35 (dt, J=9.0, 6.0Hz, 1H), 2.77-2.67 (m, 1H), 2.47-2.42 (m, 1H).

(S)-2-(4-(6-(4-chloro-2-fluorobenzyloxy)-3,5-difluoropyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4, 5-b] pyridine-5-carboxylic acid (Compound 299)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=612.9;Retention time=1.66 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.15 (t, J=10 Hz, 1H), 8.00 (d, J=8 Hz, 1H),7.93 (d, J=8.4 Hz, 1H), 7.74 (t, J=6.8 Hz, 1H), 7.64 (t, J=8 Hz, 1H),7.53-7.48 (m, 2H), 7.36 (dd, J=1.6, 6.4 Hz, 1H), 5.57 (s, 2H), 5.15-5.13(m, 1H), 4.74 (dd, J=6.4, 8.8 Hz, 1H), 4.65-4.58 (m, 2H), 4.54-4.47 (m,2H), 4.37-4.32 (m, 1H), 2.73-2.67 (m, 1H), 2.46-2.39 (m, 1H).

(S)-2-(4-(4-((5-chloropyridin-2-yl)methoxy)-5-fluoropyrimidin-2-yl)-2,5-difluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 300)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=597.1;Retention time=1.24 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.84 (d, J=2.9 Hz, 1H), 8.65 (d, J=2.1 Hz,1H), 8.05 (d, J=8.2 Hz, 1H), 8.00 (dd, J=8.4, 2.5 Hz, 1H), 7.95 (d,J=8.2 Hz, 1H), 7.76 (dd, J=10.0, 6.4 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H),7.41 (dd, J=11.1, 6.1 Hz, 1H), 5.70 (s, 2H), 5.18-5.10 (m, 1H), 4.74(dd, J=15.4, 6.8 Hz, 1H), 4.63 (d, J=16.8 Hz, 2H), 4.52 (dd, J=15.1, 6.2Hz, 2H), 4.37-4.31 (dd, J=14.9, 5.9 Hz, 1H), 2.75-2.67 (m, 1H),2.43-2.34 (m, 1H).

(S)-2-(4-(4-((5-cyano-3-fluoropyridin-2-yl)methoxy)-5-fluoropyrimidin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 301)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=588.0;Retention time=1.41 min.

¹H NMR (400 MHz, CDCl₃) δ 8.70 (s, 1H), 8.45 (t, J=11.9 Hz, 1H), 8.18(dt, J=21.0, 10.4 Hz, 2H), 8.07-7.94 (m, 2H), 7.75 (dd, J=8.7, 1.4 Hz,1H), 7.39 (t, J=7.7 Hz, 1H), 5.84 (t, J=7.0 Hz, 2H), 5.21 (s, 1H), 4.60(ddd, J=29.6, 16.5, 8.5 Hz, 4H), 4.39 (dd, J=34.6, 28.6 Hz, 2H), 2.79(d, J=8.4 Hz, 1H), 2.44 (s, 1H).

(S)-2-(4-(4-((5-cyano-3-fluoropyridin-2-yl)methoxy)-5-fluoropyrimidin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 302)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=587.9;Retention time=1.36 min.

¹H NMR (400 MHz, CD₃OD): δ 8.61 (brs, 1H), 8.46 (d, J=2.8 Hz, 1H),8.05-8.00 (m, 2H), 7.95 (d, J=8.4 Hz, 1H), 7.84 (t, J=8 Hz, 1H),7.12-7.05 (m, 2H), 5.75 (d, J=1.6 Hz, 2H), 5.16-5.12 (m, 1H), 4.65-4.56(m, 2H), 4.54-4.46 (m, 3H), 4.34-4.29 (m, 1H), 2.68-2.64 (m, 1H),2.41-2.38 (m, 1H).

(S)-2-(4-(6-(4-(JH-imidazol-1-yl)benzyloxy)pyridin-2-yl)-2,5-difluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 303)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=609.0;Retention time=1.69 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.28-8.26 (brs, 1H), 8.08 (d, J=8.2 Hz, 1H),7.97 (d, J=8.2 Hz, 1H), 7.90-7.86 (m, 1H), 7.85-7.81 (m, 1H), 7.76-7.74(m, 1H), 7.69-7.62 (m, 4H), 7.51 (d, J=6.0 Hz, 1H), 7.42 (dd, J=11.4,6.1 Hz, 1H), 7.11-7.09 (m, 1H), 6.96 (d, J=8.2 Hz, 1H), 5.52 (s, 2H),5.18-5.13 (m, 1H), 4.76 (dd, J=15.1, 6.4 Hz, 1H), 4.67-4.61 (m, 2H),4.56-4.49 (m, 2H), 4.35 (dt, J=9.0, 6.1 Hz, 1H), 2.75-2.68 (m, 1H),2.43-2.40 (m, 1H).

(S)-2-(4-(6-((4-(JH-imidazol-1-yl)benzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 304)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=591.1;Retention time=1.36 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.25-8.24 (brs, 1H), 8.06 (d, J=8.2 Hz, 1H),7.99-7.89 (m, 3H), 7.88-7.80 (m, 1H), 7.74 (t, J=1.3 Hz, 1H), 7.70-7.61(m, 5H), 7.46 (t, J=8.1 Hz, 1H), 7.10-7.09 (brs, 1H), 6.90 (d, J=8.2 Hz,1H), 5.54 (s, 2H), 5.14 (d, J=7.1 Hz, 1H), 4.73 (dd, J=15.1, 6.4 Hz,1H), 4.68-4.58 (m, 2H), 4.51 (dd, J=14.9, 10.2 Hz, 2H), 4.36 (dt, J=8.8,5.9 Hz, 1H), 2.78-2.65 (m, 1H), 2.41-2.35 (m, 1H).

(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 305)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=595.1;Retention time=1.93 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.07 (d, J=8.2 Hz, 1H), 8.02-7.87 (m, 2H),7.81 (dd, J=10.3, 8.3 Hz, 1H), 7.62 (t, J=8.2 Hz, 1H), 7.55-7.42 (m,2H), 7.39-7.26 (m, 3H), 5.55 (s, 2H), 5.11 (d, J=6.7 Hz, 1H), 4.69 (dd,J=15.0, 6.3 Hz, 1H), 4.53 (ddd, J=21.4, 18.2, 7.7 Hz, 4H), 4.35 (dd,J=14.9, 6.0 Hz, 1H), 2.67 (s, 1H), 2.44 (d, J=8.6 Hz, 1H).

(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)-3-fluorobenzyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 306)

Prepared in analogous manner as for Compound 279. LCMS: [M+H]⁺=613.0;Retention time=1.93 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.20-8.06 (m, 2H), 7.97 (d, J=8.2 Hz, 1H),7.65-7.48 (m, 3H), 7.36 (t, J=9.5 Hz, 3H), 5.47 (s, 2H), 5.14 (s, 1H),4.72 (dd, J=15.0, 6.5 Hz, 1H), 4.55 (m, J=21.6, 15.3, 5.2 Hz, 4H), 4.37(dd, J=14.9, 6.0 Hz, 1H), 2.69 (d, J=7.7 Hz, 1H), 2.45 (s, 1H).

(S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 307)

Step 1

A solution of 2-(4-bromo-3-fluoro-phenyl)acetic acid (220.7 mg, 947μmol), ethyl 4-amino-2-fluoro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate(231 mg, 861 μmol), EDCI (494.3 mg, 2.58 mmol), DIEA (669.90 mg, 5.18mmol) was stirred at 25° C. for 16 h. The resulting mixture was pouredinto water and extracted with ethyl acetate (3×20 mL). The combinedorganic layers were washed with brine (2×30 mL), dried over anhydroussodium sμLfate, concentrated and purified by silica gel chromatography(eluting with ethyl acetate/petroleum ether, v/v, 1/1) to afford ethyl4-[[2-(4-bromo-3-fluoro-phenyl)acetyl]amino]-2-fluoro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate(82 mg, 15.2% yield) as a yellow solid. LCMS: [M+H]⁺=483.0, Retentiontime=2.27 min.

Step 2

A solution of ethyl4-[[2-(4-bromo-3-fluoro-phenyl)acetyl]amino]-2-fluoro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate(82 mg, 170 μmol) in AcOH (1 mL) was stirred at 120° C. for 2 h. Theresulting mixture was concentrated to remove most solvents and adjustedpH of the solution to 7-8 with saturated sodium bicarbonate, extractedwith ethyl acetate (3×10 mL), concentrated and purified by silica gelchromatography (eluting with ethyl acetate/petroleum ether, v/v, 1/1) toafford ethyl(S)-2-(4-bromo-3-fluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(60 mg, 68.4% yield) as a yellow solid. LCMS: [M+H]⁺=465.1, Retentiontime (0.01% TFA)=2.07 min.

Step 3

A mixture of ethyl(S)-2-(4-bromo-3-fluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(105 mg, 226 μmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(63.0 mg, 248 μmol), PdCl₂(dppf)₂ (36.9 mg, 45 μmol) and KOAc (66.4 mg,677 μmol) in dioxane (2 mL) was stirred at 100° C. for 16 h undernitrogen. The resulting mixture was filtered and washed with ethylacetate, concentrated to obtain ethyl(S)-7-fluoro-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(227 mg, 204 μmol, 90.31% yield) as a brown solid and used directly forthe next stop. LCMS: [M+H]⁺=513.3, Retention time (0.01% TFA)=2.10 min.

Step 4

A mixture of ethyl(S)-7-fluoro-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(110 mg, 215 μmol),4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (65.9 mg, 215μmol), K₂CO₃ (88.9 ng, 644 μmol) and Pd(dppf)Cl₂ (17.5 mg, 21 μmol) indioxane (2 mL) was stirred at 90° C. for 3 h under nitrogen. Theresulting mixture was concentrated and purified by silica gelchromatography (eluting with ethyl acetate/petroleum ether, v/v, 1/1) toafford ethyl(S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(30 mg, 22.8% yield) as a yellow solid. LCMS: [M+H]⁺=613.0; Retentiontime=2.33 min.

Step 5

A solution of ethyl(S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(90 mg, 147 μmol), 0.5 N LiOH (2 mL) in THF (7 mL) was stirred at 25° C.for 16 h, the mixture was neutralized with acetic acid to pH=5, TheresμLting mixture was extracted with DCM/MeOH (v/v=10/1, 3×10 mL). Thecombined organic layers were concentrated and purified by prep-HPLC(Column: Xtimate C18 21.2*250 mm, 10 μm; Mobile Phase: A: water (10mMNH₄HCO₃&0.025% NH₃H₂O), B: ACN; Gradient: 5% B for 3 min, then 50-50%B in 10 min, stop at 18 min; Flow Rate (ml/min): 30.00; DetectiveWavelength (nm): 214 nm) to give(S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (17.3 mg, 20.14% yield) as a white solid. LCMS: [M+H]⁺=585.1;Retention time=1.82 min.

¹H NMR (400 MHz, DMSO-D6) δ 7.97-7.82 (m, 3H), 7.80-7.67 (m, 2H),7.62-7.50 (m, 1H), 7.46 (d, J=5.9 Hz, 1H), 7.30 (dd, J=17.4, 7.5 Hz,3H), 6.94 (d, J=8.2 Hz, 1H), 5.57 (s, 2H), 5.04 (d, J=4.9 Hz, 1H), 4.71(dd, J=15.6, 7.2 Hz, 1H), 4.61-4.31 (m, 5H), 2.72 (dt, J=16.4, 8.3 Hz,1H), 2.42 (dd, J=21.2, 12.5 Hz, 1H).

(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 308)

Prepared in analogous manner as for Compound 307. LCMS: [M+H]⁺=594.0;Retention time=1.93 min.

¹H NMR (400 MHz, DMSO-D6) δ 7.95 (t, J=8.4 Hz, 1H), 7.84 (t, J=7.9 Hz,1H), 7.61 (dd, J=16.3, 8.2 Hz, 2H), 7.46 (ddd, J=22.7, 13.4, 5.1 Hz,3H), 7.31 (dd, J=10.0, 5.9 Hz, 3H), 6.89 (d, J=8.2 Hz, 1H), 5.47 (s,2H), 5.04 (d, J=6.6 Hz, 1H), 4.75 (dd, J=15.5, 7.4 Hz, 1H), 4.65-4.32(m, 5H), 2.78-2.67 (m, 1H), 2.43 (d, J=8.4 Hz, 1H).

(S)-2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 309)

Prepared in analogous manner as for Compound 307. LCMS: [M+H]⁺=594.0;Retention time=1.96 min.

¹H NMR (400 MHz, MeOD) δ 7.74 (dd, J=11.5, 9.2 Hz, 2H), 7.69-7.57 (m,2H), 7.48-7.36 (m, 2H), 7.35-7.18 (m, 2H), 7.10 (dd, J=14.0, 4.9 Hz,2H), 6.70 (d, J=8.2 Hz, 1H), 5.43 (s, 2H), 5.12 (d, J=5.5 Hz, 1H), 4.66(dd, J=15.4, 7.2 Hz, 1H), 4.61-4.54 (m, 1H), 4.54-4.44 (m, 2H),4.42-4.25 (m, 2H), 3.55 (d, J=3.1 Hz, 2H), 2.80-2.64 (m, 1H), 2.49-2.36(m, 1H).

(S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 310)

Prepared in analogous manner as for Compound 307. LCMS: [M+H]⁺=585.1;Retention time=1.85 min.

¹H NMR (400 MHz, DMSO-D6) δ 7.89 (dd, J=22.8, 9.2 Hz, 4H), 7.75 (d,J=11.0 Hz, 2H), 7.64 (dd, J=16.6, 7.0 Hz, 2H), 7.50-7.26 (m, 2H), 6.93(d, J=8.2 Hz, 1H), 5.62 (s, 2H), 5.10 (s, 1H), 4.76 (s, 1H), 4.66-4.29(m, 5H), 2.75 (s, 1H), 2.43 (s, 1H).

(S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-2-yl)-2-fluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 311)

Prepared in analogous manner as for Compound 307. LCMS: [M+H]⁺=595.2;Retention time (0.01% TFA)=1.64 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.73 (d, J=5.2 Hz, 1H), 8.09-7.98 (m, 2H),7.82 (d, J=5.2 Hz, 1H), 7.63 (dd, J=16.6, 8.4 Hz, 2H), 7.56-7.46 (m,2H), 7.43-7.28 (m, 2H), 5.53 (s, 2H), 5.09 (d, J=7.0 Hz, 1H), 4.78 (dd,J=15.6, 7.2 Hz, 1H), 4.67-4.28 (m, 5H), 2.80-2.70 (m, 1H), 2.44 (d,J=8.9 Hz, 1H).

(S)-2-(4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidin-2-yl)-2-fluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 312)

Prepared in analogous manner as for Compound 307. LCMS: [M+H]⁺=603.9;Retention time=1.53 min

¹H NMR (400 MHz, CDCl₃) δ 8.44-8.43 (d, J=2.4 Hz, 1H), 8.11-8.05 (m,2H), 7.93-7.89 (t, J=8.0 Hz, 1H), 7.70-7.66 (t, J=7.6 Hz, 1H), 7.63-7.61(d, J=8.0 Hz, 1H), 7.51-7.47 (t, J=8.0 Hz, 2H), 7.45-7.42 (d, J=9.2 Hz,1H), 5.71 (s, 2H), 5.22-5.20 (d, J=6.8 Hz, 1H), 4.71-4.47 (m, 6H), 2.82(s, 1H), 2.47 (s, 1H).

(S)-2-(4-(4-((5-cyanopyridin-2-yl)methoxy)-5-fluoropyrimidin-2-yl)-2,5-difluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 313)

Prepared in analogous manner as for Compound 307. LCMS: [M+H]⁺=605.2;Retention time (10 mM NH₄HCO₃)=1.18 min.

(S)-2-((1-(6-(4-cyano-2-fluorobenzyloxy) pyridin-2-yl)piperidin-4-ylidene) methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo [4, 5-b]pyridine-5-carboxylic acid (Compound 314)

Step 1

A mixture of 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (10g, 30.93 mmol), piperidin-4-one (3.99 g, 40.21 mmol), Pd₂(dba)₃ (1.13 g,1.55 mmol), BINAP (1.93 g, 3.09 mmol) and Cs2CO3 (15.08 g, 46.40 mmol)in Toluene (80 mL) was stirred for 18 h at 110° C. under Argon, untilthe reaction was complete as indicated by LCMS, the reaction mixture wasfiltered through a pad of Celite with EtOAc, and the combined organicswere concentrated in vacuo, purified by silica gel chromatography(Hexanes/EtOAc=77:23) to give the desired product3-fluoro-4-[[6-(4-oxo-1-piperidyl)-2-pyridyl] oxymethyl] benzonitrile(5.25 g, 52.2% yield) as a pale yellow solid. LCMS: [M+H]⁺=326.2;Retention time=1.63 min.

¹H NMR (400 MHz, CDCl₃) δ 7.62 (t, J=7.6 Hz, 1H), 7.50-7.42 (m, 2H),7.37 (dd, J=1.2, 8 Hz, 1H), 6.32 (d, J=8 Hz, 1H), 6.23 (d, J=7.6 Hz,1H), 5.44 (s, 2H), 3.85 (t, J=6 Hz, 4H), 2.46 (t, J=6 Hz, 4H).

Step 2

To a suspension of tert-butyl 2-dimethoxyphosphorylacetate (7.13 g,31.81 mmol) in THF (60 mL) was added slowly LDA (3.98 g, 37.12 mmol, 19mL) at rt and stirred for 10 min under Ar. A solution of3-fluoro-4-[[6-(4-oxo-1-piperidyl)-2-pyridyl] oxymethyl] benzonitrile(3.45 g, 10.60 mmol) in THF (15 mL) was added drop-wise at rt. Aftercompletion of the reaction as judged by LCMS, the reaction mixture wasquenched with water (10 mL) and extracted with EtOAc (3×20 mL). Theorganic phase was washed with brine (50 mL) and dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude product waspurified by flash chromatography (SiO₂, hexane/ethyl acetate 10:1) toafford tert-butyl 2-[1-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-4-piperidylidene] acetate (2.2 g, 36.1% yield) as acolorless liquid. LCMS: [M+H]⁺=424.2; Retention time=1.98 min.

Step 3

A mixture of tert-butyl 2-[1-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-4-piperidylidene]acetate (2.2 g, 5.20 mmol) in DCM(21 mL) was added TFA (10.36 g, 90.86 mmol, 7 mL), and stirred for 1 hat rt, until the reaction was complete as indicated by LCMS, thereaction mixture was added DCM (160 mL), washed with Aqueous Sat. NaHCO₃(2×30 mL), dried and evaporated, purified by flash chromatography onsilica gel (PE:EA/0%˜66%) to give the desired product2-[1-[6-[(4-cyano-2-fluoro-phenyl) methoxy]-2-pyridyl]-4-piperidylidene]acetic acid (1.78 g, 4.44 mmol, 85.5% yield) as a pale white solid.LCMS: [M+H]⁺=368.1; Retention time=1.25 min.

Step 4

A mixture of 2-[1-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-4-piperidylidene] acetic acid (723 mg, 1.97 mmol) inTHF (30 mL) was stirred and cooled on salt-ice bath. Then isobutylchloroformate (525.00 mg, 3.84 mmol) and N-methylmorpholine (598 mg,5.91 mmol, 0.65 mL) were added, and the reaction was stirred at salt-icebath for 20 min. Tert-butyl 5-amino-6-[[(2S)-oxetan-2-yl] methylamino]pyridine-2-carboxylate (500 mg, 1.79 mmol) was dissolved in pyridine(6.85 g, 86.55 mmol, 7 mL) and N-methylmorpholine (598 mg, 5.91 mmol,0.65 mL) were added to the reaction mixture on an ice-bath with stirring1 h at 0° C. After reaction completion, the solvent was evaporated invacuo and the remaining residue was partitioned with DCM (50 mL) andwater (20 mL). The DCM layer was washed once with brine, dried overanhydrous Na₂SO₄, filtered and evaporated in vacuo to give a crudeproduct. The crude was purified by silica gel chromatography(Hexanes/EtOAc=20:1) to give the desired product tert-butyl5-[[2-[1-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-4-piperidylidene] acetyl]amino]-6-[[(2S)-oxetan-2-yl] methylamino] pyridine-2-carboxylate (168mg, 13.35% yield) as a pale yellow solid. LCMS: [M+H]⁺=629.1; Retentiontime=2.12 min.

Step 5

A mixture of tert-butyl 5-[[2-[1-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-4-piperidylidene]acetyl]amino]-6-[[(2S)-oxetan-2-yl] methylamino] pyridine-2-carboxylate (64 mg,102 μmol) and AcOH (102 μmol) in Toluene (4 mL) was stirred for 1.5 h at60° C., until the reaction was complete as indicated by LCMS, thereaction mixture was concentrated in vacuo, purified by prep-TLC(PE:EA/1:1.5) to give the desired product tert-butyl2-[[1-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-4-piperidylidene] methyl]-3-[[(2S)-oxetan-2-yl]methyl] imidazo [4, 5-b] pyridine-5-carboxylate (5 mg, 8.0% yield) as apale yellow oil. LCMS: [M+H]⁺=612.3; Retention time (0.01% TFA)=2.04min.

Step 6

A mixture of tert-butyl 2-[[1-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-4-piperidylidene]methyl]-3-[[(2S)-oxetan-2-yl]methyl] imidazo [4, 5-b] pyridine-5-carboxylate (5 mg, 8 μmol) in DCM (4mL) was added TFA (1.48 g, 13.0 mmol, 1 mL), and stirred for 1 h at rt,until the reaction was complete as indicated by LCMS, the reactionmixture was were concentrated in vacuo, dissolved in THF (1.5 mL),purified by prep-HPLC to give the desired product2-[[1-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-4-piperidylidene] methyl]-3-[[(2S)-oxetan-2-yl]methyl] imidazo [4, 5-b] pyridine-5-carboxylic acid (1.1 mg, 23.3%yield) as a white solid. LCMS: [M+H]+=555.0; Retention time=1.51 min.

¹H NMR (400 MHz, DMSO-D6-d6) δ 8.16-8.09 (m, 1H), 7.68 (t, J=8 Hz, 1H),7.62-7.55 (m, 2H), 7.52 (t, J=8 Hz, 1H), 6.70 (s, 1H), 6.41 (d, J=8.4Hz, 1H), 6.18 (d, J=8 Hz, 1H), 5.49 (s, 2H), 5.28 (dd, J=2.8, 2.4 Hz,1H), 4.82-4.80 (m, 1H), 4.74-4.68 (m, 1H), 4.63-4.60 (m, 1H), 4.46-4.41(m, 1H), 3.74 (dd, J=4.4, 2 Hz, 2H), 3.68 (t, J=5.6 Hz, 2H), 2.95 (t,J=5.6 Hz, 2H), 2.81-2.76 (m, 1H), 2.56-2.54 (m, 1H), 2.50 (t, J=5.2 Hz,2H).

(S)-2-((1-(6-(2,4-difluorobenzyloxy)pyridin-2-yl)piperidin-4-ylidene)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 315)

Prepared in analogous manner as for Compound 314. LCMS: [M+H]⁺=548.0;Retention time (0.01% TFA)=1.97 min

¹H NMR (400 MHz, MeOD) δ 8.15 (d, J=16.0 Hz, 2H), 7.48-7.47 (brs, 2H),6.97 (d, J=8.2 Hz, 2H), 6.70-6.69 (brs, 1H), 6.41-6.40 (brs, 1H),6.13-6.12 (brs, 1H), 5.38 (s, 2H), 5.33-5.28 (m, 1H), 4.77-4.76 (brs,1H), 4.64-4.63 (brs, 1H), 3.79-3.78 (brs, 1H), 3.73-3.72 (brs, 1H),3.02-3.01 (brs, 2H), 2.78-2.77 (brs, 1H), 2.56-2.55 (brs, 3H), 2.06-2.05(brs, 2H), 0.92-0.91 (brs, 2H).

(S)-2-((1-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperidin-4-ylidene)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 316)

Prepared in analogous manner as for Compound 314. LCMS: [M+H]⁺=538.2;Retention time (0.01% TFA)=1.74 min.

¹H NMR (400 MHz, CDCl₃) δ 8.85-8.83 (m, 1H), 8.26-8.18 (m, 2H),7.95-7.91 (m, 1H), 7.60-7.54 (m, 1H), 7.48-7.44 (m, 1H), 6.22-6.20 (m,1H), 6.17-6.14 (m, 1H), 5.57-5.54 (m, 1H), 5.52 (s, 2H), 5.20-5.18 (m,1H), 4.67-4.58 (m, 3H), 4.41-4.35 (m, 1H), 3.95-3.83 (m, 4H), 3.69-3.58(m, 2H), 2.81-2.79 (m, 1H), 2.47-2.42 (m, 1H), 2.21-2.20 (m, 2H).

(S)-2-((1-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-4-ylidene)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 317)

Prepared in analogous manner as for Compound 314. LCMS: [M+H]⁺=554.0;Retention time=1.31 min.

¹H NMR δ 8.18 (s, 1H), 7.88 (d, J=9.8 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H),7.70-7.66 (m, 2H), 7.58 (d, J=8.4 Hz, 1H), 7.50-7.45 (m, 1H), 6.29 (d,J=8.2 Hz, 1H), 6.10 (d, J=7.8 Hz, 1H), 5.57-5.53 (brs, 1H), 5.42 (s,2H), 5.02-4.96 (m, 1H), 4.62-4.57 (m, 1H), 4.51-4.43 (m, 2H), 4.35-4.30(m, 1H), 3.91-3.84 (m, 2H), 3.82-3.71 (m, 2H), 3.65-3.58 (m, 3H),2.68-2.64 (m, 1H), 2.19-2.12 (m, 2H).

(S)-2-((1-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperidin-4-ylidene)methyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 318)

Step 1

A solution of tert-butyl4-(2-ethoxy-2-oxo-ethylidene)piperidine-1-carboxylate (1.0 g, 3.71 mmol)in THF (10 mL) and Ethanol (8 mL). Lithium hydroxide hydrate (779 mg,18.56 mmol) in Water (7 mL) was added. The mixture was stirred at 50° C.for 16 h, the mixture was neutralized with acetic acid to pH=5 and theresulting mixture was extracted with EtOAc (2×50 mL). The combinedorganic layers were concentrated to give2-(1-tert-butoxycarbonyl-4-piperidylidene)acetic acid (0.9 g, 3.54 mmol,95.4% yield). LCMS: [M+Na]+=264.1, Retention time (0.01% TFA)=1.75 min.

Step 2

A solution of ethyl4-amino-2-fluoro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (207 mg, 772μmol), 2-(1-tert-butoxycarbonyl-4-piperidylidene)acetic acid (204.79 mg,889 μmol), T₃P (736.08 mg, 2.31 mmol) and Et₃N (311.72 mg, 3.09 mmol) inDMF (5 mL), the mixture was stirred at 30° C. for 16 h. The resultingmixture was poured into water and extracted with ethyl acetate (3×20mL). The combined organic layers were washed with brine (2×50 mL), driedover anhydrous sodium sulfate, concentrated and purified by silica gelchromatography (eluting with ethyl acetate/petroleum ether, v/v, 3/2) toafford tert-butyl(S)-4-(2-((4-(ethoxycarbonyl)-3-fluoro-2-((oxetan-2-ylmethyl)amino)phenyl)amino)-2-oxoethylidene)piperidine-1-carboxylate(135 mg, 27.4% yield) as a yellow oil. LCMS: [M+H]⁺=492.3, Retentiontime (0.01% TFA)=2.07 min.

Step 3

A solution of tert-butyl4-[2-[4-ethoxycarbonyl-3-fluoro-2-[[(2S)-oxetan-2-yl]methylamino]anilino]-2-oxo-ethylidene]piperidine-1-carboxylate(64 mg, 130 μmol) in Toluene (2 mL) was stirred at 120° C. for 16 h. Theresulting mixture was concentrated and purified by silica gelchromatography (eluting with ethyl acetate/petroleum ether, v/v, 4/1) toafford ethyl(S)-2-((1-(tert-butoxycarbonyl)piperidin-4-ylidene)methyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(46 mg, 74.6% yield) as a yellow oil. LCMS: [M+H]⁺=474.3, Retention time(0.01% TFA)=1.97 min.

Step 4

To a solution of ethyl(S)-2-((1-(tert-butoxycarbonyl)piperidin-4-ylidene)methyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(20 mg, 41 μmol) in DCM (5 mL) was added TFA (8.5 mg, 75 μmol). Themixture was stirred at rt for 2 h. The resulting mixture wasconcentrated and adjusted to pH-8 with sat. sodium bicarbonate,extracted with dichloromethane, dried over anhydrous sodium sulfate andconcentrated to afford ethyl(S)-7-fluoro-1-(oxetan-2-ylmethyl)-2-(piperidin-4-ylidenemethyl)-1H-benzo[d]imidazole-6-carboxylate(10 mg, 27 μmol, 65.8% yield) as a yellow oil. LCMS: [M+H]⁺=374.2;Retention time (0.1% TFA)=0.89 min.

Step 5

A solution of ethyl(S)-7-fluoro-1-(oxetan-2-ylmethyl)-2-(piperidin-4-ylidenemethyl)-1H-benzo[d]imidazole-6-carboxylate(40 mg, 107 μmol),6-[(6-bromo-2-pyridyl)oxymethyl]pyridine-3-carbonitrile (31.08 mg, 107μmol), Pd₂(dba)₃ (9.8 mg, 11 μmol), BINAP (13.3 mg, 21 μmol) and Cs₂CO₃(104.8 mg, 321 μmol) in Toluene (2 mL) in glove box was stirred at 110°C. for 16 h. The resulting solution was filtered and purified by silicagel chromatography (eluting with ethyl acetate/petroleum ether, v/v,4/1) to afford ethyl(S)-2-((1-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperidin-4-ylidene)methyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(63 mg, 66.6% yield) as a yellow oil. LCMS: [M+H]⁺=583.3; Retention time(0.1% TFA)=1.36 min.

Step 6

A solution of ethyl(S)-2-((1-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperidin-4-ylidene)methyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(60 mg, 103 μmol) and LiOH (0.1N) (86.5 mg, 2.06 mmol) in THF (10 mL)was stirred at rt for 6 h. The resulting mixture was neutralized withacetic acid to pH=5 and extracted with DCM/MeOH (v/v=10/1, 3×10 mL). Thecombined organic layers were concentrated and purified by prep-HPLC togive(S)-2-((1-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperidin-4-ylidene)methyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (3.7 mg, 6.5% yield) as a white solid. LCMS: [M+H]⁺=555.2;Retention time (0.1% FA)=1.88 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.98 (d, J=1.3 Hz, 1H), 8.26 (dd, J=8.2, 2.1Hz, 1H), 7.90-7.71 (m, 1H), 7.57 (t, J=7.9 Hz, 2H), 7.48 (t, J=8.0 Hz,1H), 7.35 (d, J=8.4 Hz, 1H), 6.27 (d, J=8.2 Hz, 1H), 6.16 (d, J=7.7 Hz,1H), 5.51 (s, 1H), 5.43 (s, 2H), 5.00 (s, 1H), 4.62 (dd, J=15.5, 7.4 Hz,1H), 4.54-4.39 (m, 2H), 4.34 (dt, J=8.8, 6.0 Hz, 1H), 3.73 (dd, J=25.8,15.9 Hz, 3H), 2.68 (d, J=6.8 Hz, 2H), 2.39 (dd, J=22.8, 14.1 Hz, 2H),2.10 (s, 2H).

(S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)cyclohexyl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 319)

Step 1

Trifluoromethylsulfonyl trifluoromethanesulfonate (2.39 g, 8.46 mmol,1.42 mL) was added dropwise to a solution of2,6-ditert-butyl-4-methyl-pyridine (2.17 g, 10.58 mmol) inDichloromethane (16 mL) followed by the dropwise addition of a solutionof methyl 2-(4-oxocyclohexyl)acetate (1.2 g, 7.05 mmol) inDichloromethane (16 mL). The reaction mixture was allowed to stir at 25°C. for 16 h and then concentrated to give methyl2-[4(trifluoromethylsμLfonyloxy)cyclohex-3-en-1-yl]acetate (1.48 g,66.1% yield) as a colorless oil. LCMS: [M+H]⁺=591, Retention time (10 mMNH₄HCO₃)=2.35 min.

Step 2

A mixture of methyl2-[4-(trifluoromethylsμLfonyloxy)cyclohex-3-en-1-yl]acetate (700 mg,2.32 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(646.9 mg, 2.55 mmol), Pd(dppf)Cl₂ (94.6 mg, 116 μmol), potassiumacetate (681.84 mg, 6.95 mmol), Pd(dppf)Cl₂ (64.2 mg, 116 μmol) inDioxane (1 mL) was exchanged in glove box. The reaction mixture wasstirred at 80° C. for 17 h. LCMS indicated the reaction was complete.Silica gel (3 g) was added into the reaction mixture and evaporated togive a dry powder, which was purified through silica gel. Methyl2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl]acetate(546 mg, 1.85 mmol, 80.0% yield) was obtained as light-yellow solid.LCMS: [M+H]⁺=280, Retention time (0.01% TFA)=2.16 min.

Step 3

A mixture of [4-(2-methoxy-2-oxo-ethyl)cyclohexen-1-yl]boronic acid (443mg, 2.13 mmol), 2-bromo-6-[(4-chloro-2-fluoro-phenyl)methoxy]pyridine(672.8 mg, 2.13 mmol), dipotassium carbonate (881.2 mg, 6.38 mmol),Pd(dppf)Cl₂ (77.7 mg, 106 μmol) in Dioxane (6 mL) was bubbled withnitrogen for 10 min, and then stirred at 80° C. for 16 h. LCMS indicatedthe reaction was almost complete. Methyl2-[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]cyclohex-3-en-1-yl]acetate(361 mg, 833 μmol, 39.2% yield) was obtained as white solid. LCMS:[M+H]⁺=390, Retention time (10 mmol NH₄HCO₃)=2.49 min.

Step 4

To a solution of methyl2-[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]cyclohex-3-en-1-yl]acetate(351 mg, 810 μmol) in Methanol (50 mL) was added Raney nickel (0.5 g,5.84 mmol). The reaction mixture was stirred at 20° C. for 2 h. LCMSindicated the reaction mixture was complete. The reaction mixture wasfiltered through celite, washed with ethyl acetate. The filtrate wasevaporated under reduced pressure to give methyl2-[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]cyclohexyl]acetate(331 mg, 718 μmol, 88.6% yield) as white solid. LCMS: [M+H]⁺=392,Retention time (0.01% TFA)=2.42 min.

Step 5

To a solution of methyl2-[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]cyclohexyl]acetate(330 mg, 716 μmol) in THF (3 mL) in ice-bath was added dropwise asolution of Lithium hydroxide hydrate (150.2 mg, 3.58 mmol) in Water (3mL). The reaction mixture was stirred at 50° C. for 16 h.2-[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]cyclohexyl]aceticacid (180 mg, 453 μmol, 63.2% yield) was obtained as light-yellow oil.LCMS: [M+H]⁺=378; Retention time (0.01% TFA)=2.20 min.

Step 6

To a solution of2-[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]cyclohexyl]aceticacid (137 mg, 344 μmol), methyl4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (81.38 mg, 344 μmol),3-hydroxytriazolo[4,5-b]pyridine (56.26 mg, 413 μmol),3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine; hydrochloride(79.24 mg, 413 μmol) in DMF (1 mL) was stirred at 25° C. for 1 hr. LCMSindicated the reaction was complete. The reaction mixture was dilutedwith brine (10 mL) and extracted with ethyl acetate (3×10 mL). Thecombined organic layers were dried over sodium sulfate and evaporatedunder reduced pressure to provide a residue, which was purified throughsilica gel to give tert-butyl2-[[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]cyclohexyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate(180 mg, 80.1% yield) as colorless oil. LCMS: [M+H]⁺=638, Retention time(0.01% TFA)=2.41 min.

Step 7

A solution of tert-butyl4-[[2-[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]cyclohexyl]acetyl]amino]-3-[[(2S)-oxetan-2-yl]methylamino]benzoate(175 mg, 261 μmol) in acetic acid (3 mL) was stirred at 60° C. for 2 h.LCMS indicated the reaction was complete. The reaction mixture wasflushed slowly with nitrogen until the solvent was removed. Methyl(S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)cyclohexyl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(127 mg, 74.7% yield) was obtained as light-yellow oil. LCMS:[M+H]⁺=620, Retention time (0.01% TFA)=2.04 min.

Step 8

Methyl(S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)cyclohexyl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(122 mg, 187 μmol) was dissolved in Dichloromethane (2 mL) and2,2,2-trifluoroacetic acid (21.3 mg, 187 μmol). The reaction mixture wasstirred at 25° C. for 0.5 h. LCMS indicated the reaction was complete.The solvents were removed completely. The residue was basified with sat.Ammonium bicarbonate solution until pH=5, extracted with dichloromethane(3×10 mL). The combined organic layers were dried over sodium sulfateand evaporated under reduced pressure.2-(((1r,4S)-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)cyclohexyl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylicacid was obtained (60 mg, 54.1% yield) as a brown solid. LCMS:[M+H]⁺=564, Retention time (0.01% TFA)=1.85 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.68 (s, 1H), 8.20 (s, 1H), 7.87 (d, J=41.1Hz, 2H), 7.61 (s, 1H), 7.47-7.16 (m, 3H), 7.08 (s, 1H), 6.92 (d, J=36.3Hz, 1H), 5.48 (s, 2H), 5.09 (d, J=49.3 Hz, 2H), 4.87 (s, 1H), 4.47 (s,2H), 3.37 (s, 1H), 2.87 (s, 1H), 2.46-2.36 (m, 2H), 2.08 (s, 2H), 1.91(s, 2H), 1.68 (d, J=67.4 Hz, 6H).

(S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorophenyl)amino)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid(Compound 320)

Step 1

To a solution of 4-bromo-2-fluoro-aniline (3.8 g, 20.00 mmol) in ethanol(40 mL) were added CS₂ (4.57 g, 60.00 mmol, 3.60 mL) and DABCO (13.46 g,120.00 mmol). The reaction mixture was stirred at rt overnight. Theresulting precipitate was collected by filtration, washed with ice-coldethanol, and dried to yield a pale yellow solid, which was used in thenext step without further characterization and purification. Triphosgene(2.97 g, 10.00 mmol) was added slowly to a solution of the pale yellowsolid in DCM (50 mL) at 0° C. The reaction mixture was stirred at thistemperature for an additional 1 h and then heated at 40° C. for 4 h; thereaction was quenched with water. The crude was extracted with CH₂Cl₂(3×50 mL) and then dried over MgSO₄, concentrated and the residue waspurified by flash column chromatograph over silica gel, eluting withpetroleum ether to afford 4-bromo-2-fluoro-1-isothiocyanato-benzene (3.6g, 15.20 mmol, 76.0% yield). Retention time (0.01% TFA)=2.26 min.

Step 2

A suspension of tert-butyl4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (115 mg, 413 μmol) inDCM (2 mL) were added 4-bromo-2-fluoro-1-isothiocyanato-benzene (108.4mg, 467 μmol), EDCI (89.5 mg, 467 μmol) and DIEA (60.3 mg, 467 μmol).The reaction mixture was stirred at 40° C. for 16 h until TLC showedthat the reaction was complete. The reaction mixture was evaporatedunder reduced pressure and the residue was purified by flash columnchromatograph over silica gel eluting with CH₂Cl₂/MeOH (20:1) to givetert-butyl(S)-2-((4-bromo-2-fluorophenyl)amino)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(99 mg, 50.3% yield) as a pale yellow solid. LCMS: [M+H]⁺=476, Retentiontime (0.01% TFA)=2.05 min.

Step 3

A mixture of tert-butyl(S)-2-((4-bromo-2-fluorophenyl)amino)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(100 mg, 210 μmol), potassium acetate (61.8 mg, 630 μmol),Bis(pinacolato)diboron (53.3 mg, 210 μmol), Pd(dppf)Cl₂ complex with DCM(8.6 mg, 11 μmol) in anhydrous dioxane (0.5 mL) was stirred at 80° C.for 16 h. The reaction was complete as indicated by LCMS, the reactionmixture was filtered through a pad of celite, washed with ethyl acetateseveral times and the combined organics were concentrated in vacuo togive crude tert-butyl(S)-2-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(109.9 mg, 209.9 mmol, 82% yield) as a black oil which was used for nextstep directly. LCMS: [M+H]⁺=524; Retention time (0.01% TFA)=2.10 min.

Step 4

A mixture of tert-butyl(S)-2-((2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(110 mg, 210 μmol),4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (64.54 mg, 210μmol), Pd(dppf)Cl₂ complex with DCM (8.6 mg, 11 μmol) and K₂CO₃ (87.1mg, 630 μmol) in dioxane (2 mL) was stirred under N₂ at 80° C. for 16 h.The mixture was filtered and concentrated in vacuo to give the crudeproduct tert-butyl(S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorophenyl)amino)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(120 mg, 91.6% yield) as a black oil. LCMS: [M+H]+=624.1; Retention time(0.01% TFA)=2.48 min.

Step 5

To a solution of tert-butyl(S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorophenyl)amino)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(100 mg, 160 μmol) in DCM (1 mL) was added slowly 2,2,2-trifluoroaceticacid (91.4 mg, 801.7 μmol) at 0° C. and stirred for 16 h at roomtemperature. After completion of the reaction as judged by LCMS, thereaction mixture was filtered and concentrated in vacuo. The crudeproduct was purified by prep-HPLC and lyophilized to afford(S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorophenyl)amino)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (27 mg, 29.7% yield) as a white solid. LCMS: [M+H]⁺=568.1;Retention time=1.89 min.

¹H NMR (400 MHz, DMSO-D6-d6) δ 9.36 (1H, s), 8.47 (1H, d, J=8.4), 8.07(1H, s), 7.96-7.92 (3H, m), 7.90-7.70 (4H, m), 7.63 (1H, d, J=7.5), 7.49(1H, d, J=8.2), 6.87 (1H, d, J=8.1), 5.63 (2H, s), 5.23 (1H, s),4.72-4.44 (4H, m), 2.82-2.65 (1H, m), 2.45-2.31 (1H, s).

(S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorophenoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 321)

Step 1

A mixture of methyl 2-oxo-1,3-dihydrobenzimidazole-5-carboxylate (1.6 g,8.33 mmol) and phosphoryl trichloride (25.53 g, 166.52 mmol, 15.47 mL)was stirred for 3 h at 100° C., until the reaction was complete asindicated by LCMS, the reaction mixture was concentrated in vacuo. Theresidue was cooled to 0° C., and cold, saturated aqueous NaHCO₃ (30 mL)was added cautiously. After stirring at rt for 15 min, the mixture wassonicated and the resulting residue was filtered to yield the titledcompound methyl 2-chloro-3H-benzimidazole-5-carboxylate (1.3 g, 67.5%yield), which was used in the next step without further purification.LCMS: [M+H]⁺=211.1; Retention time (0.01% TFA)=1.61 min.

Step 2

A mixture of methyl 2-chloro-3H-benzimidazole-5-carboxylate (1 g, 4.32mmol), 4-bromo-2-fluoro-phenol (2.48 g, 12.96 mmol, 1.42 mL) andN-ethyl-N-isopropyl-propan-2-amine (1.68 g, 12.96 mmol, 2.26 mL) wasstirred for 3 h at 150° C., until the reaction was complete as indicatedby LCMS, the reaction mixture was concentrated in vacuo, purified bysilica gel chromatography (petroleum ether/EtOAc gradient 0-50%) to givethe desired product methyl2-(4-bromo-2-fluoro-phenoxy)-3H-benzimidazole-5-carboxylate (700 mg,36.8% yield) as white solid. LCMS: [M+H]+=365.0; Retention time (0.01%TFA)=1.92 min.

Step 3

A mixture of methyl2-(4-bromo-2-fluoro-phenoxy)-3H-benzimidazole-5-carboxylate (843.4 mg,1.92 mmol) and dipotassium carbonate (397.4 mg, 2.88 mmol) in NMP (9 mL)was stirred for 1 h at room temperature, then [(2S)-oxetan-2-yl]methyl4-methylbenzenesμLfonate (696.7 mg, 2.88 mmol) was added to the mixtureand stirred for 16 h at 80° C. The mixture was purified by Prep-HPLC toafford (product 1) methyl2-(4-bromo-2-fluoro-phenoxy)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate(4) (135 mg, 307 μmol, 16.0% yield) (NBK0059-76-P2) and (product 2)methyl2-(4-bromo-2-fluoro-phenoxy)-1-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate(5) (150 mg, 17.6% yield) (NBK0059-76-P1). Product 1: LCMS:[M+H]⁺=437.1; Retention time (0.01% TFA)=1.91 min. Product 2: LCMS:[M+H]⁺=437.1; Retention time (0.01% TFA)=1.89 min.

Step 4

A mixture of methyl2-(4-bromo-2-fluoro-phenoxy)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate(4) (85 mg, 195 μmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(49.6 mg, 195 μmol), potassium acetate (38.3 mg, 391 μmol) andcyclopentyl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(16.0 mg, 20 μmol) in dioxane (2 mL) was stirred for 2 h at 90° C.,until the reaction was complete as indicated by LCMS, the reactionmixture was used in next step without purification. LCMS: [M+H]+=483.3;Retention time=2.11 min; (also observed the hydrolyzed correspondingBoronic acid [M+H]+=401.2; Retention time=1.63 min.

Step 5

Sodium carbonate (62.0 mg, 585 μmol) (2M in water) andcyclopentyl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(15.92 mg, 20 μmol) were added to the mixture obtained methyl(S)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylateand the mixture was stirred for 2 h at 90° C., until the reaction wascomplete as indicated by LCMS, the reaction mixture was filtered througha pad of celite with EtOAc. The combined organics were concentrated invacuo, purified by silica gel column (petroleum ether/EtOAc gradient0-50%) to give the desired product methyl(S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorophenoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(110 mg, 88.2% yield). LCMS: [M+H]+=583.2; Retention time (10 mMNH₄HCO₃)=2.12 min.

Step 6

To a stirred solution of methyl2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenoxy]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate(100 mg, 156 μmol) in THF (5 mL) was added lithium hydroxide hydrate(0.5 M) (65.6 mg, 1.56 mmol). The reaction mixture was stirred at 30° C.for 16 h and upon completion of the reaction, as judged by LCMS, themixture was acidified with HOAc until pH ˜6 and purified by prep-HPLC toafford(S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorophenoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (34.2 mg, 60 μmol, 38.5% yield) as a white solid. LCMS:[M+H]⁺=669.2.

¹H NMR (400 MHz, DMSO-D6) δ 8.20 (d, J=1.2 Hz, 1H), 8.11 (dd, J=12.1,2.0 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.97-7.83 (m, 2H), 7.81-7.67 (m,5H), 7.46 (d, J=8.4 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H), 5.64 (s, 2H), 5.16(s, 1H), 4.72-4.41 (m, 3H), 4.33 (dt, J=9.0, 6.0 Hz, 1H), 2.87-2.66 (m,1H), 2.53 (s, 1H).

(S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-2′-oxo-[2,4′-bipyridin]-1′(2′H)-yl)methyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 322)

Step 1

To a solution of ethyl4-amino-2-fluoro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (500 mg, 1.77mmol), 2-chloro-1,1,1-trimethoxy-ethane (288.1 mg, 1.77 mmol) inacetonitrile (5 mL) was added 4-methylbenzenes Lfonic acid hydrate (33.7mg, 177 μmol). The reaction mixture was stirred at 60° C. for 1.5 hr.LCMS indicated the reaction was completed. Silica gel (1 g) was addedinto the reaction mixture, and the mixture was evaporated under reducedpressure to provide a dry powder, which was purified through silica gelto give ethyl(S)-2-(chloromethyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(600 mg, 98.5% yield) as white solid. LCMS: [M+H]⁺=327; Retention time(10 mM NH₄HCO₃)=1.98 min.

Step 2

A mixture of 4-bromo-1H-pyridin-2-one (124.7 mg, 717 μmol), ethyl2-(chloromethyl)-4-fluoro-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate(239 mg, 717 μmol), cesium carbonate (233.6 mg, 717 μmol) in DMF (3 mL)was stirred at 25° C. for 2 h. LCMS indicated the reaction was complete.The reaction mixture was diluted with saturated ammonium chloridesolution, extracted with ethyl acetate (3×4 mL). The combined organiclayers were washed with brine (3×4 mL), dried with anhydrous sodiumsulfate and evaporated under reduce pressure to provide a residue, whichwas purified through silica gel (petroleum ether/EtOAc gradient50%-100%) to give ethyl(S)-2-(chloromethyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(320 mg, 91.3% yield) as light-yellow gum. LCMS: [M+H]⁺=464. Retentiontime (10 mM NH₄HCO₃)=1.96 min.

Step 3

A mixture of ethyl ethyl(S)-2-(chloromethyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(200 mg, 409 μmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(114.3 mg, 450 μmol), potassium acetate (120.5 mg, 1.23 mmol),Bis(triphenylphosphine)palladium(II) chloride (28.7 mg, 41 μmol) inDioxane (5 mL) was charged under nitrogen in glovebox. The reactionmixture was then stirred at 80° C. for 4 h. LCMS indicated the reactionwas complete, and the reaction mixture was cooled down, into which4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (132.3 mg, 409μmol), dipotassium carbonate (169.7 mg, 1.23 mmol), Pd(dppf)Cl₂ (29.9mg, 41 μmol) were added. The reaction mixture was bubbled with nitrogenfor 2 min. The resulting mixture was stirred at 80° C. for 16 h. LCMSindicated the reaction was complete. Silica gel (2 g) was added into thereaction mixture, and the solvent was removed under reduced pressure toprovide a dry powder which was purified through silica gel (eluent:petroleum ether/ethyl acetate gradient 33-100%) to give ethyl(S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-2′-oxo-[2,4′-bipyridin]-1′(2′H)-yl)methyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(220 mg, 323.7 μmol, 79.1% yield, 90% purity) as white solid. LCMS:[M+H]⁺=612; Retention time (10 mM NH₄HCO₃)=1.98 min.

Step 4

A solution of ethyl(S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-2′-oxo-[2,4′-bipyridin]-1′(2′H)-yl)methyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate(220 mg, 324 μmol) in THF (5 mL) was added a solution of Lithiumhydroxide hydrate (67.9 mg, 1.62 mmol) in Water (8 mL). LCMS indicatedthe reaction mixture was completed. The reaction mixture was acidifiedwith acetic acid until pH=5. Tetrahydrofuran was removed under reducedpressure. The aqueous phase was extracted with ethyl acetate (3×20 mL).The combined organic layers was dried and evaporated under reducedpressure to provide a residue which was purified through prep-HPLC togive(S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-2′-oxo-[2,4′-bipyridin]-1′(2′H)-yl)methyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (95.5 mg, 49.0% yield). LCMS: [M+H]⁺=584; Retention time (0.01%TFA)=1.84 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.04-7.84 (m, 3H), 7.79-7.68 (m, 3H),7.67-7.54 (m, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.09 (d, J=1.7 Hz, 1H), 7.03(d, J=8.2 Hz, 1H), 6.96 (dd, J=7.2, 1.9 Hz, 1H), 5.50 (dd, J=61.4, 17.0Hz, 4H), 5.11 (d, J=6.8 Hz, 1H), 4.89 (dd, J=15.5, 7.0 Hz, 1H), 4.73 (d,J=12.8 Hz, 1H), 4.58-4.46 (m, 1H), 4.40 (dd, J=6.1, 2.9 Hz, 1H),2.86-2.70 (m, 1H), 2.44 (d, J=9.1 Hz, 1H).

(S)-2-((6-((4-chloro-2-fluorobenzyl)oxy)-2′-oxo-[2,4′-bipyridin]-1′(2′H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 323)

Prepared in analogous manner as for Compound 322. LCMS: [M+H]⁺=575.0;Retention time=1.52 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.28 (s, 1H), 7.98 (d, J=7.2 Hz, 1H),7.90-7.86 (m, 1H), 7.82-7.79 (m, 1H), 7.70 (d, J=7.4 Hz, 1H), 7.63-7.59(m, 2H), 7.50 (dd, J=10.0, 2.0 Hz, 1H), 7.33 (dd, J=8.2, 1.7 Hz, 1H),7.12-7.11 (m, 1H), 7.01-6.98 (m, 2H), 5.60-5.43 (m, 4H), 5.11-5.07 (m,1H), 4.88-4.83 (m, 1H), 4.74-4.70 (m, 1H), 4.52-4.47 (m, 1H), 4.39-4.34(m, 1H), 2.75-2.71 (m, 1H), 2.41-2.36 (m, 1H).

(S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-2′-oxo-[2,4′-bipyridin]-1′(2′H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 324)

Prepared in analogous manner as for Compound 322. LCMS: [M+H]⁺=567.0;Retention time=1.40 min.

¹H NMR (400 MHz, DMSO-D6-D6) δ 8.09-8.07 (d, J=8.0 Hz, 1H), 7.98-7.96(t, J=5.6 Hz, 2H), 7.93-7.87 (m, 2H), 7.77-7.70 (m, 3H), 7.08-7.02 (m,2H), 6.97-6.94 (dd, J₁=7.2 Hz, J₂=2.0 Hz, 1H), 5.67-5.49 (m, 4H),5.18-5.12 (m, 1H), 4.87-4.81 (m, 1H), 4.74-4.69 (m, 1H), 4.53-4.47 (m,1H), 4.39-4.33 (m, 1H), 2.77-2.68 (m, 1H), 2.44-2.36 (m, 1H).

(S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidin-2-yl)-2-oxopyridin-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (Compound 325)

Prepared in analogous manner as for Compound 322. LCMS: [M+H]⁺=586.2;Retention time=1.18 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.85 (d, J=2.8 Hz, 1H), 8.10-7.93 (m, 4H),7.88-7.73 (m, 2H), 7.29 (d, J=1.8 Hz, 1H), 7.11 (dd, J=7.1, 1.9 Hz, 1H),5.79 (brs, 2H), 5.68 (d, J=16.1 Hz, 1H), 5.53 (d, J=16.1 Hz, 1H),5.22-5.09 (m, 1H), 4.84 (dd, J=15.0, 6.2 Hz, 1H), 4.71 (dd, J=15.0, 3.2Hz, 1H), 4.50 (dd, J=13.8, 7.6 Hz, 1H), 4.36 (dt, J=8.9, 6.0 Hz, 1H),2.78-2.64 (m, 1H), 2.44-2.31 (m, 1H).

2-(4-(6-(4-chloro-2-fluorobenzyloxy)pyridin-2-yl)-2-fluorobenzyl)-3-(oxetan-2-ylmethyl)-2H-indazole-5-carboxylicacid (Compound 326)

Step 1

A mixture of 3,4-dihydro-2H-pyran (327.19 mg, 3.89 mmol), methyl3-iodo-3a,7a-dihydro-1H-indazole-5-carboxylate (1.18 g, 3.89 mmol),4-methylbenzenes Lfonic acid hydrate (739.9 mg, 3.89 mmol) in DCM (50mL) was stirred for 12 h at 30° C. under N₂, until the reaction wascomplete as indicated by LCMS, the reaction mixture was poured intowater and extracted with EtOAc, and the combined organics wereconcentrated in vacuum, purified by silica gel chromatography(Hexanes/EtOAc=10:1) to give the desired product methyl3-iodo-1-tetrahydropyran-2-yl-3a,7a-dihydroindazole-5-carboxylate (0.9g, 59.6% yield) as pale yellow solid. LCMS: [M+H]+=387; Retentiontime=2.00 min.

Step 2

A mixture of 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 mg,1.79 mmol), methyl 3-iodo-1-tetrahydropyran-2-yl-indazole-5-carboxylate(300 mg, 777 μmol), Pd(dppf)Cl₂ (10 mg) and sodium carbonate (300.0 mg,2.83 mmol) in water (1 mL) and dioxane (4 mL) was stirred for 2 h at100° C. under N₂, the reaction mixture was monitored by LCMS. Thereaction mixture was filtered through a pad of celite with EtOAc andwashed with water, the combined organics were concentrated in vacuum,purified by silica gel chromatography (Hexanes/EtOAc=10:1) to give thedesired product methyl3-allyl-1-tetrahydropyran-2-yl-indazole-5-carboxylate (170 mg, 72.9%yield) as pale yellow solid. LCMS: [M+H]⁺=301; Retention time=2.14 min.

Step 3

A mixture of 3-chlorobenzenecarboperoxoic acid (2.76 g, 15.98 mmol),methyl 3-allyl-1-tetrahydropyran-2-yl-indazole-5-carboxylate (2.4 g,7.99 mmol) in DCM (20 mL) was stirred for 16 h at 20° C. under N2, thereaction mixture was monitored by LCMS. The reaction mixture wasfiltered through a pad of celite with EtOAc, and the combined organicswere concentrated in vacuum, purified by silica gel chromatography(Hexanes/EtOAc=5:1) to give the desired product methyl3-(oxiran-2-ylmethyl)-1-tetrahydropyran-2-yl-indazole-5-carboxylate (1.4g, 55.4% yield) as pale yellow solid. LCMS: [M+H]⁺=317; Retentiontime=1.78 min.

Step 4

A mixture of BLAH methane iodide (3.48 g, 15.81 mmol), potassium2-methylpropan-2-olate (1.77 g, 15.81 mmol) and methyl3-(oxiran-2-ylmethyl)-1-tetrahydropyran-2-yl-indazole-5-carboxylate (500mg, 1.58 mmol, 280.37 mL), dichloro copper (21.3 mg, 158 μmol) in t-BuOH(50 mL) was stirred in an oil bath of 80° C. for 2 h, the reaction wasmonitored by LCMS. The reaction mixture was adjusted to pH=1 with HCl,the aqueous layer was extracted with DCM, dried over Na₂SO₄ andconcentrated, and purified by prep-HPLC to give the desired product3-(oxetan-2-ylmethyl)-1-tetrahydropyran-2-yl-indazole-5-carboxylic acid(200 mg, 24.0% yield) as pale yellow solid. LCMS: [M+H]⁺=317; Retentiontime=1.47 min.

Step 5

A mixture of3-(oxetan-2-ylmethyl)-1-tetrahydropyran-2-yl-indazole-5-carboxylic acid(30 mg, 94.8 μmol) iodomethane (14.8 mg, 104.3 μmol, 6.5 μL, 100%purity) and dipotassium; carbonate (39.3 mg, 284.5 μmol, 17.2 μL, 100%purity) in DMF (5 mL) was stirred for 1 hr at 25° C. in a round bottomflask under N2, until the reaction was complete as indicated by LCMS,the reaction mixture was filtered through a pad of Celite with EtOAc,and the combined organics were concentrated in vacuo, purified by silicagel chromatography to give the desired product methyl3-(oxetan-2-ylmethyl)-1-tetrahydropyran-2-yl-indazole-5-carboxylate (22mg, 47.8 μmol, 50.4% yield, 71.8% purity) as colorless oil. LCMS[M+H]⁺=331.1; Retention time (0.01% TFA)=1.82 min.

Step 6

A mixture of methyl3-(oxetan-2-ylmethyl)-1-tetrahydropyran-2-yl-indazole-5-carboxylate (120mg, 363 μmol), 2,2,2-trifluoroacetic acid (1.48 g, 12.98 mmol, 1 mL) inDCM (2 mL) was stirred at 20° C. for 2 h, the reaction was monitored byLCMS. The reaction mixture was concentrated to give the desired productmethyl 3-(oxetan-2-ylmethyl)-1H-indazole-5-carboxylate (100 mg, 89.4%yield) as pale yellow solid. LCMS: [M+H]⁺=247; Retention time=1.47 min.

Step 7

A mixture of methyl 3-(oxetan-2-ylmethyl)-1H-indazole-5-carboxylate (100mg, 406 μmol), 4-bromo-1-(bromomethyl)-2-fluoro-benzene (108.8 mg, 406μmol) and potassium carbonate (168.4 mg, 1.22 mmol) in DMF (10 mL) wasstirred in an oil bath of 60° C. for 2 h, the reaction was monitored byLCMS. The reaction mixture was filtered through a pad of celite withEtOAc, and the combined organics were concentrated in vacuum, purifiedby silica gel chromatography (Hexanes/EtOAc=5:1) give the desiredproduct methyl1-[(4-bromo-2-fluoro-phenyl)methyl]-3-(oxetan-2-ylmethyl)indazole-5-carboxylate(80 mg, 45.5% yield) as pale yellow solid. LCMS: [M+H]⁺=433; Retentiontime=1.47 min.

Step 8

A mixture of 2-bromo-6-[(4-chloro-2-fluoro-phenyl)methoxy]pyridine (1.6g, 5.05 mmol) Butyllithium (356.14 mg, 5.56 mmol, 2.5 mL) andtributyl(chloro)stannane (1.97 g, 6.07 mmol, 1.65 mL) in THF (10 mL) wasstirred for 16 h at 30° C. under N₂, the reaction mixture was monitoredby LCMS. The reaction mixture was poured into water and extracted withEtOAc, and the combined organics were concentrated in vacuum, purifiedby silica gel chromatography (Hexanes/EtOAc=10:1) to give the desiredproducttributyl-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]stannane (300mg, 18.8% yield) as pale yellow solid. LCMS: [M+H]⁺=528; Retentiontime=2.14 min.

Step 9

A mixture oftributyl-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]stannane (60.8mg, 115 μmol), methyl2-[(4-bromo-2-fluoro-phenyl)methyl]-3-(oxetan-2-ylmethyl)indazole-5-carboxylate(50 mg, 115 μmol) and Pd(PPh₃)₄ (115 μmol) in DMF (1 mL) was stirred for2 h at 130° C. under N₂, the reaction mixture was monitored by LCMS. Thereaction mixture was filtered through a pad of celite with EtOAc, andthe combined organics were concentrated in vacuum, purified by silicagel chromatography (Hexanes/EtOAc=2:1) to give the desired productmethyl2-[[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]methyl]-3-(oxetan-2-ylmethyl)indazole-5-carboxylate(50 mg, 73.4% yield) as pale yellow solid. LCMS: [M+H]⁺=590; Retentiontime=1.99 min.

Step 10

A mixture of methyl2-[[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]methyl]-3-(oxetan-2-ylmethyl)indazole-5-carboxylate(50 mg, 84.7 μmol), Lithium hydroxide hydrate (400 mg, 9.53 mmol) in THF(2 mL), Methanol (2 mL) and Water (2 mL) was stirred for 2 h at 25° C.under N₂, the reaction mixture was monitored by LCMS. LCMS shows workwell. The reaction mixture was adjusted to pH=1 with HCl, extracted withDCM and the combined organics were concentrated in vacuum, afterPREP-HPLC purification to give the desired product1-[[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]methyl]-3-(oxetan-2-ylmethyl)indazole-5-carboxylicacid (20.3 mg, 35 μmol, 41.6% yield). LCMS: [M+H]+=576; Retentiontime=1.50 min.

¹H NMR (400 MHz, CDCl₃) δ 8.66 (s, 1H), 8.13 (ddd, J=10.3, 7.0, 1.3 Hz,2H), 7.60 (ddd, J=8.4, 7.1, 2.0 Hz, 1H), 7.45 (dd, J=8.3, 6.6 Hz, 2H),7.28 (d, J=1.1 Hz, 1H), 7.19-7.00 (m, 3H), 6.90 (ddd, J=7.1, 5.1, 0.9Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 5.69 (s, 2H), 5.43 (s, 2H), 5.38-5.24(m, 1H), 4.74-4.61 (m, 1H), 4.59-4.45 (m, 1H), 3.47 (ddd, J=32.1, 14.5,6.2 Hz, 2H), 2.72 (d, J=5.6 Hz, 1H), 2.57 (d, J=8.9 Hz, 1H).

2-((6-((4-chloro-2-fluorobenzyl)oxy)-3′,6′-dihydro-[2,4′-bipyridin]-1′(2′H)-yl)methyl)-3-(oxazol-4-ylmethyl)imidazo[1,2-a]pyridine-6-carboxylicacid (Compound 327)

Step 1

A mixture of methyl 6-aminopyridine-3-carboxylate (17.62 g, 115.81mmol), 1,3-dibromopropan-2-one (25 g, 115.81 mmol) in EtOH (400 mL) wasstirred for 12 h at 80° C. under N₂, until the reaction was complete asindicated by LCMS, the reaction mixture added was NaHCO₃ and filteredthrough a pad of Celite with EtOAc, and the combined organics wereconcentrated in vacuo, purified by silica gel chromatography(Hexanes/EtOAc=12:1) to give the desired product methyl2-(bromomethyl)imidazo[1,2-a]pyridine-6-carboxylate (5.2 g, 16.7% yield)as pale yellow solid. LCMS: [M+H]⁺=269.0; Retention time (0.01%TFA)=0.99 min.

Step 2

A mixture of methyl 2-(bromomethyl)imidazo[1,2-a]pyridine-6-carboxylate(6.9 g, 25.64 mmol) and potassium acetate (7.55 g, 76.92 mmol, 4.81 mL)in DMF (150 mL) was stirred for 2 h at 50° C. under N₂, until thereaction was complete as indicated by LCMS, the reaction mixture wasfiltered through a pad of Celite with EtOAc, and the combined organicswere concentrated in vacuo, purified by silica gel chromatography(Hexanes/EtOAc=5:1) to give the desired product methyl2-(acetoxymethyl)imidazo[1,2-a]pyridine-6-carboxylate (5.8 g, 91.1%yield) as pale yellow solid. LCMS: [M+H]⁺=249.1; Retention time (0.01%TFA)=0.95 min.

Step 3

A mixture of phosphoryl trichloride (11.74 g, 76.54 mmol) in DMF (50 mL)was stirred for 0.5 h at 0° C. under N₂, and methyl2-(acetoxymethyl)imidazo[1,2-a]pyridine-6-carboxylate (3.8 g, 15.31mmol) was then added and the mixture was stirred for 2 h at rt until thereaction was complete as indicated by LCMS, the reaction mixture wasfiltered through a pad of Celite with EtOAc, and the combined organicswere concentrated in vacuo, purified by silica gel chromatography(Hexanes/EtOAc=6:1) to give the desired product methyl2-(acetoxymethyl)-3-formyl-imidazo[1,2-a]pyridine-6-carboxylate (2.4 g,56.78% yield) as pale yellow solid. LCMS: [M+H]+=277.2; Retention time(0.01% TFA)=1.58 min.

Step 4

A mixture of methyl2-(acetoxymethyl)-3-formyl-imidazo[1,2-a]pyridine-6-carboxylate (2.4 g,8.69 mmol) and potassium carbonate (1.80 g, 13.03 mmol) in MeOH (50 mL)was stirred for 1.5 h at rt under N₂, until the reaction was complete asindicated by LCMS, the reaction mixture was filtered through a pad ofCelite with DCM, and the combined organics were concentrated in vacuo,purified by silica gel chromatography (Hexanes/EtOAc=2:1) to give thedesired product methyl3-formyl-2-(hydroxymethyl)imidazo[1,2-a]pyridine-6-carboxylate (2.1 g,87.7% yield) as pale yellow solid.

LCMS: [M+H]⁺=235.1; Retention time (0.01% TFA)=1.08 min.

Step 5

A mixture of methyl3-formyl-2-(hydroxymethyl)imidazo[1,2-a]pyridine-6-carboxylate (2.1 g,8.97 mmol), tert-butyl-chloro-diphenyl-silane (2.96 g, 10.76 mmol, 2.76mL), and imidazole (1.83 g, 26.90 mmol) in DCM (40 mL) was stirred for 2hr at rt under N₂, until the reaction was complete as indicated by LCMS,the reaction mixture was filtered through a pad of Celite with EtOAc,and the combined organics were concentrated in vacuo, purified by silicagel chromatography (Hexanes/EtOAc=8:1) to give the desired productmethyl2-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-formyl-imidazo[1,2-a]pyridine-6-carboxylate(5.8 g, 89.0% yield) as pale yellow solid. LCMS: [M+H]⁺=473.0; Retentiontime (0.01% TFA)=2.36 min.

Step 6

A mixture of oxazole (1.46 g, 21.16 mmol) butyllithium (1.08 g, 16.93mmol) in THF (30 mL) was stirred for 0.5 h at −78° C. under N₂, methyl2-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-formyl-imidazo[1,2-a]pyridine-6-carboxylate(1 g, 2.12 mmol) was then added and the resulting mixture was furtherstirred for 2 h at −78° C. under N₂, until the reaction was complete asindicated by LCMS. The reaction mixture was filtered through a pad ofCelite with EtOAc, and the combined organics were concentrated in vacuo,purified by prep-HPLC to give the desired product methyl2-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-(oxazol-4-ylmethyl)imidazo[1,2-a]pyridine-6-carboxylate(500 mg, 45.0% yield) as pale white solid. LCMS: [M+H]⁺=542.0; Retentiontime (0.01% TFA)=1.75 min.

Step 7

A mixture of methyl2-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-[hydroxy(oxazol-4-yl)methyl]imidazo[1,2-a]pyridine-6-carboxylate(800 mg, 1.48 mmol), triethylsilane (1.72 g, 14.77 mmol, 2.36 mL) in TFA(20 mL) was stirred for 16 h at 65° C. under N₂, until the reaction wascomplete as indicated by LCMS. The reaction mixture was concentrated andneutralized with NaHCO₃, and the resulting residue was dissolved in DCM,filtered through a pad of Celite with DCM and MeOH, and the combinedorganics were concentrated in vacuo to give the desired product methyl2-(hydroxymethyl)-3-(oxazol-4-ylmethyl)imidazo[1,2-a]pyridine-6-carboxylate(105 mg, 24.8% yield) as pale yellow oil. LCMS: [M+H]⁺=288.0; Retentiontime=1.30 min.

Step 8

To a stirred solution of methyl2-(hydroxymethyl)-3-(oxazol-4-ylmethyl)imidazo[1,2-a]pyridine-6-carboxylate(30 mg, 104 μmol) in DCM (10 mL) solution was added methanes Lfonicanhydride (21.8 mg, 125 μmol) TEA (31.7 mg, 313 μmol). The reactionmixture was stirred at rt for 3 h and upon completion of the reaction,as judged by TLC, the mixture was diluted with DCM (50 mL) and warmed toroom temperature. The layers were separated, and the aqueous layer wasextracted with DCM (2×50 mL). The combined organic phase was washed withbrine (50 mL) and dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo to afford methyl2-(methylsμLfonyloxymethyl)-3-(oxazol-4-ylmethyl)imidazo[1,2-a]pyridine-6-carboxylate(30 mg, 51.5% yield) as a light-yellow liquid. LCMS: [M+H]⁺=366.0;Retention time (10 mM NH₄HCO₃)=1.38 min.

Step 9

A mixture of methyl2-(bromomethyl)-3-(oxazol-4-ylmethyl)imidazo[1,2-a]pyridine-6-carboxylate(115.0 mg, 49 μmol),2-[(4-chloro-2-fluoro-phenyl)methoxy]-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridine(18.8 mg, 59 μmol), N-ethyl-N-isopropyl-propan-2-amine (31.8 mg, 246μmol) in 1,4-dioxane (12 mL) was stirred for 1.5 hr at 95° C. under N₂,until the reaction was complete as indicated by LCMS. The reactionmixture was filtered through a pad of Celite with EtOAc, and thecombined organics were concentrated in vacuo, purified by silica gelchromatography (DCM:MeOH=20:1) to give the desired product methyl2-[[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-(oxazol-4-ylmethyl)imidazo[1,2-a]pyridine-6-carboxylate(10 mg, 34.5% yield) as pale yellow oil. LCMS: [M+H]⁺=588.0; Retentiontime (0.01% TFA)=2.12 min.

Step 10

A mixture of methyl2-[[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-(oxazol-4-ylmethyl)imidazo[1,2-a]pyridine-6-carboxylate(10 mg, 17 μmol), lithium hydroxide (1.2 mg, 51 μmol) in MeOH (1 mL),H2O (3 mL) and THF (3 mL) was stirred for 2 h at rt under N₂, until thereaction was complete as indicated by LCMS. The reaction mixture wasfiltered through a pad of Celite with EtOAc, and the combined organicswere concentrated in vacuo, purified by prep-HPLC to give the desiredproduct2-[[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-(oxazol-4-ylmethyl)imidazo[1,2-a]pyridine-6-carboxylicacid (2 mg, 20.5% yield) as pale white solid. LCMS: [M+H]⁺=574.1;Retention time=1.56 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.79-8.78 (brs, 1H), 8.02 (t, J=11.2 Hz,1H), 7.74-7.64 (m, 2H), 7.51 (ddd, J=12.8, 12.0, 5.1 Hz, 3H), 7.30 (dd,J=8.2, 1.8 Hz, 1H), 7.09 (d, J=0.7 Hz, 1H), 7.04 (d, J=7.4 Hz, 1H),6.76-6.62 (m, 2H), 5.39 (s, 2H), 4.76 (s, 2H), 3.82 (s, 2H), 3.18-3.17(brs, 2H), 2.66 (t, J=5.5 Hz, 2H), 2.40-2.39 (brs, 2H).

(S)-(2-((6-((4-cyano-2-fluorobenzyl)oxy)-3′,6′-dihydro-[2,4′-bipyridin]-1′(2′H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)boronicacid (Compound 328)

Step 1

A mixture of 4-bromo-2-fluoro-1-nitro-benzene (2 g, 9.09 mmol),4-methylbenzenes Lfonic acid, [(2S)-oxetan-2-yl]methanamine (2.36 g,9.09 mmol), N,N-diethylethanamine (4.60 g, 45.46 mmol) in DMF (50 mL)was stirred for 2 h at 60° C. under N₂ until the reaction was completeas indicated by LCMS. The reaction mixture was filtered through a pad ofcelite with EtOAc, and the combined organics were concentrated in vacuo,purified by silica gel chromatography to give the desired product5-bromo-2-nitro-N-[[(2S)-oxetan-2-yl]methyl]aniline (2.42 g, 7.58 mmol,83.4% yield, 89.8% purity) as yellow solid. LCMS: [M+H]⁺=289.0;Retention time (0.01% TFA)=1.72 min.

Step 2

A mixture of 5-bromo-2-nitro-N-[[(2S)-oxetan-2-yl]methyl]aniline (2.42g, 8.44 mmol) Iron (3.77 g, 67.54 mmol) and ammonia hydrochloride (3.61g, 67.54 mmol) in Ethanol (16 mL) and Water (4 mL) was stirred for 1.5 hat 80° C. in a RBF under N₂, until the reaction was completed asindicated by LCMS, the reaction mixture was filtered through a pad ofCelite with EtOAc, and the combined organics were concentrated in vacuo,purified by silica gel chromatography to give the desired product4-bromo-N2-[[(2S)-oxetan-2-yl]methyl]benzene-1,2-diamine (1.44 g, 5.56mmol, 65.8% yield, 99.5% purity) as brown oil. LCMS: [M+H]⁺=259.1;Retention time (0.01% TFA)=1.16 min.

Step 3

A mixture of 4-bromo-N2-[[(2S)-oxetan-2-yl]methyl]benzene-1,2-diamine(1.4 g, 5.44 mmol), 2-chloro-1,1,1-trimethoxy-ethane (925.9 mg, 5.99mmol) and 4-methylbenzenes Lfonic acid hydrate (103.6 mg, 544.5 μmol) inACN (30 mL) was stirred for 1 h at 60° C. under N₂ until the reactionwas complete as indicated by LCMS, the reaction mixture was filteredthrough a pad of Celite with EtOAc, and the combined organics wereconcentrated in vacuo, purified by silica gel chromatography to give thedesired product6-bromo-2-(chloromethyl)-1-[[(2S)-oxetan-2-yl]methyl]benzimidazole (1.04g, 2.37 mmol, 43.6% yield) as white solid. LCMS: [M+H]⁺=317.0; Retentiontime (0.01% TFA)=1.45 min.

Step 4

A mixture of6-bromo-2-(chloromethyl)-1-[[(2S)-oxetan-2-yl]methyl]benzimidazole (500mg, 1.58 mmol),3-fluoro-4-[[6-(1,2,3,6-tetrahydropyridin-4-yl)-2-pyridyl]oxymethyl]benzonitrile(735.1 mg, 2.38 mmol), N-ethyl-N-isopropyl-propan-2-amine (1.43 g, 11.09mmol) and sodium iodide dihydrate (28.8 mg, 158.4 μmol) in dioxane (20mL) was stirred for 16 h at 90° C. in a RBF under N₂, until the reactionwas completed as indicated by LCMS, the reaction mixture was filteredthrough a pad of Celite with EtOAc, and the combined organics wereconcentrated in vacuo, purified by silica gel chromatography to give thedesired product4-[[6-[1-[[6-bromo-1-[[(2S)-oxetan-2-yl]methyl]benzimidazol-2-yl]methyl]-3,6-dihydro-2H-pyridin-4-yl]-2-pyridyl]oxymethyl]-3-fluoro-benzonitrile(800 mg, 869.65 μmol, 54.9% yield) as white solid. LCMS: [M+H]⁺=588.0;Retention time (10 mM NH₄HCO₃)=1.82 min.

Step 5

A solution of4-[[6-[1-[[6-bromo-1-[[(2S)-oxetan-2-yl]methyl]benzimidazol-2-yl]methyl]-3,6-dihydro-2H-pyridin-4-yl]-2-pyridyl]oxymethyl]-3-fluoro-benzonitrile(20 mg, 33.99 μmol) and hypoboric acid (9.1 mg, 102 μmol),dicyclohexyl-[2-(2,4,6-triisopropylphenyl) phenyl]phosphane (0.3 mg, 0.7μmol), XPhos Pd G₃ (0.3 mg, 0.34 μmol) potassium acetate (20 mg, 203.9μmol) in Ethanol (3 mL) and ethyleneglycol (0.15 mL), and the mixturewas stirred at 60° C. for 3 h. The reaction mixture was purified by HPLCto give the desired product[2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazol-5-yl]boronicacid (2 mg, 2.7 μmol, 8.0% yield) as a white solid. LCMS: [M+H]⁺=554.1;Retention time (0.01% TFA)=1.72 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.16 (s, 2H), 8.01 (s, 1H), 7.89 (d, J=10.4Hz, 1H), 7.75-7.61 (m, 4H), 7.54 (d, J=8.0 Hz, 1H), 7.10 (d, J=7.4 Hz,1H), 6.77 (d, J=8.2 Hz, 1H), 6.71 (s, 1H), 5.49 (s, 2H), 5.14-5.03 (m,1H), 4.71 (dd, J=15.1, 7.1 Hz, 1H), 4.57 (dd, J=15.1, 3.4 Hz, 1H), 4.47(dd, J=14.1, 7.1 Hz, 1H), 4.38 (dt, J=9.0, 6.0 Hz, 1H), 4.04 (d, J=13.3Hz, 1H), 3.89 (d, J=13.3 Hz, 1H), 3.22 (d, J=9.2 Hz, 3H), 2.76-2.64 (m,3H), 2.44-2.30 (m, 2H).

(S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3′,6′-dihydro-[3,4′-bipyridin]-1′(2′H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 329)

Step 1

A suspension of (4-chloro-2-fluoro-phenyl)methanol (1 g, 6.23 mmol) andpotassium 2-methylpropan-2-olate (768.7 mg, 6.85 mmol) in THF (20 mL)was stirred for 0.5 h at 0° C. under N₂. Then 3-bromo-2-fluoro-pyridine(1.21 g, 6.85 mmol) was added slowly and stirred for 1 h under N₂. Aftercompletion of the reaction as judged by LCMS, reaction mixture wasquenched with water (20 mL) and extracted with EtOAc (3×20 mL). Theorganic phase was washed with brine (50 mL) and dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude product waspurified by flash chromatography to afford3-bromo-2-[(4-chloro-2-fluoro-phenyl)methoxy]pyridine (1.4 g, 4.04 mmol,64.9% yield) as yellow oil. LCMS: [M+H]⁺=315.9; Retention time (0.01%TFA)=2.30 min.

Step 2

A mixture of 3-bromo-2-[(3-chloro-2-fluoro-phenyl)methoxy]pyridine(184.3 mg, 582 μmol), methyl3-[[(2S)-oxetan-2-yl]methyl]-2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]methyl]benzimidazole-5-carboxylate(272.1 mg, 582 μmol), Pd(dppf)Cl₂ (42.6 mg, 58 μmol) and K₂CO₃ (241.4mg, 1.75 mmol) in dioxane (10 mL) and Water (2 mL) was stirred for 16 hat 90° C. under N₂ until the reaction was complete as indicated by LCMS.The reaction mixture was filtered through a pad of Celite with EtOAc andthe combined organics were concentrated in vacuo, purified by silica gelchromatography to give the desired product methyl2-[[4-[2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate(200 mg, 227.5 μmol, 39.1% yield, 68.7% purity) as brown oil. LCMS:[M+H]⁺=577.3; Retention time (0.01% TFA)=1.63 min.

Step 3

A mixture of methyl2-[[4-[2-[(4-chloro-2-fluoro-phenyl)methoxy]-3-pyridyl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate(200 mg, 207.96 μmol) and LiOH (43.6 mg, 1.04 mmol) in THF (2.5 mL),Methanol (2.5 mL) and Water (1.5 mL) was stirred for 1.5 h at 25° C.under N₂, until the reaction was complete as indicated by LCMS. Thereaction mixture was purified by HPLC to give the desired product2-[[4-[2-[(4-chloro-2-fluoro-phenyl)methoxy]-3-pyridyl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylicacid (12.4 mg, 22.02 μmol, 10.6% yield) as white solid. LCMS:[M+H]⁺=563.0; Retention time (10 mM NH₄HCO₃)=1.59 min.

¹H NMR (400 MHz, MeOD) δ 8.27-8.26 (brs, 1H), 8.05 (dd, J=5.0, 1.8 Hz,1H), 7.98 (d, J=8.5 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.58 (dd, J=7.3,1.8 Hz, 1H), 7.51 (t, J=8.1 Hz, 1H), 7.34-7.16 (m, 2H), 6.97 (dd, J=7.3,5.0 Hz, 1H), 5.92-5.91 (brs, 1H), 5.43 (s, 2H), 5.24 (d, J=4.9 Hz, 1H),4.87 (dd, J=15.3, 7.1 Hz, 1H), 4.69 (dd, J=15.4, 2.7 Hz, 1H), 4.60 (dd,J=13.7, 7.9 Hz, 1H), 4.46 (dt, J=9.0, 5.9 Hz, 1H), 4.12 (d, J=13.6 Hz,1H), 4.00 (d, J=13.6 Hz, 1H), 3.27-3.14 (m, 2H), 2.84-2.68 (m, 3H),2.60-2.41 (m, 3H).

2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydropyridin-1(2H)-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 330)

Step 1

To a suspension of 3-bromobenzene-1,2-diol (1.20 g, 6.37 mmol) intoluene (100 mL) were added 1-(4-chloro-2-fluoro-phenyl)ethanone (1 g,5.79 mmol) and 4-methylbenzenesulfonic acid hydrate (1.10 g, 5.79 mmol).The reaction apparatus was fitted with a Dean-Stark trap, and thereaction mixture was heated at 140° C. for 60 h, whereupon the solutionwas concentrated in vacuo and purified by flash chromatography to afford4-bromo-2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxole (280 mg,774.2 μmol, 13.4% yield) as yellow oil. LCMS [M+H]⁺=343.0; Retentiontime (0.01% TFA)=2.07 min.

Step 2

To a stirred solution of4-bromo-2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxole (100 mg,291.06 μmol) in 1,4-Dioxane (10 mL) and water (2 mL) were added methyl3-[[(2S)-oxetan-2-yl]methyl]-2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]methyl]benzimidazole-5-carboxylate(142.8 mg, 305 μmol), Pd(dppf)Cl₂ (21.3 mg, 29 μmol) and K₂CO₃ (80.3 mg,582 μmol). The reaction mixture was stirred at 100° C. for 2 h. Uponcompletion of the reaction as judged by TLC, the mixture was dilutedwith EtOAc (100 mL) and warmed to room temperature. The layers wereseparated, and the aqueous layer was extracted with EtOAc (2×50 mL). Thecombined organic phase was washed with brine (50 mL) and dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to afford the crudeproduct methyl2-[[4-[2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate(150 mg, 206.2 μmol, 70.9% yield) as a light-yellow liquid which wasused directly in the next step. LCMS: [M+H]⁺=604.0, Retention time (10mM NH₄HCO₃)=2.31 min.

Step 3

To a stirred solution of methyl2-[[4-[2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate(150 mg, 206.2 μmol) in THF (3 mL), MeOH (3 mL) and water (3 mL) wasadded LiOH.H₂O (31.3 mg, 744 μmol). The reaction mixture was stirred atrt for 8 h. Upon completion of the reaction as judged by TLC, themixture was diluted with EtOAc (100 mL) and warmed to room temperature.The layers were separated, and the aqueous layer was extracted withEtOAc (2×50 mL). The combined organic phase was washed with brine (50mL) and dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The crude product was purified by prep-HPLC to afford2-[[4-[2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylicacid (53.9 mg, 91 μmol, 44.3% yield) as a white solid. LCMS:[M+H]⁺=590.0, Retention time (10 mM NH₄HCO₃)=1.68 min.

¹H NMR (400 MHz, MeOD) δ 8.35-8.34 (brs, 1H), 8.00 (dd, J=8.5, 1.4 Hz,1H), 7.71 (d, J=8.5 Hz, 1H), 7.58 (t, J=8.3 Hz, 1H), 7.30 (dd, J=10.9,1.9 Hz, 1H), 7.26-7.20 (m, 1H), 6.84 (dt, J=15.4, 7.2 Hz, 2H), 6.80-6.73(m, 1H), 6.41-6.40 (brs, 1H), 5.26 (d, J=8.1 Hz, 1H), 4.87-4.86 (brs,1H), 4.74 (d, J=14.0 Hz, 1H), 4.63 (dd, J=14.0, 7.7 Hz, 1H), 4.48 (dd,J=14.7, 5.7 Hz, 1H), 4.19 (d, J=14.0 Hz, 1H), 4.07 (d, J=13.9 Hz, 1H),3.32-3.25 (m, 2H), 2.88 (d, J=5.7 Hz, 2H), 2.83-2.74 (m, 1H), 2.63-2.62(brs, 2H), 2.58-2.48 (m, 1H), 2.05 (s, 3H).

(S)-2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)thiazol-5-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 331)

Step 1

To a mixture of 4-bromothiazole (2 g, 12.2 mmol) in 4-bromothiazole (2g, 12.19 mmol) was added sodium hydroxide (2.93 g, 73.2 mmol). And thenthe mixture was stirred at 150° C. for 4 h under N₂ atmosphere. Thereaction mixture was diluted with water and then extracted with EtOAc(3×50 mL), the organic was concentrated to yield the residue which waspurified by silica gel chromatography (petroleum ether:EtOAc=95:5) togive the 4-[(4-chloro-2-fluoro-phenyl)methoxy]thiazole (370 mg, 1.52mmol, 12.5% yield). LCMS: [M+H]⁺=244.1; Retention time (0.01% TFA)=1.77min.

Step 2

To a mixture of 4-[(4-chloro-2-fluoro-phenyl)methoxy]thiazole (60 mg,246 μmol) in THF (5 mL) was added 1-bromopyrrolidine-2,5-dione (65.7 mg,369.3 μmol). And then the mixture was stirred at rt for 3 h under N₂atmosphere. The reaction mixture was diluted with water and extractedwith DCM (3×20 mL) and then concentrated to yield a residue which waspurified by silica gel chromatography (petroleum ether:EtOAc=98:2) togive the 5-bromo-4-[(4-chloro-2-fluoro-phenyl)methoxy]thiazole (60 mg,186.0 μmol, 75.5% yield). LCMS: [M+H]⁺=322.0; Retention time (0.01%TFA)=1.96 min.

Step 3

To a mixture of 5-bromo-4-[(4-chloro-2-fluoro-phenyl)methoxy]thiazole(30 mg, 93.00 μmol) and methyl3-[[(2S)-oxetan-2-yl]methyl]-2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]methyl]benzimidazole-5-carboxylate(52.2 mg, 111.6 μmol) in Water (1 mL) and 1,4-dioxane (5 mL) were addedPd(dppf)Cl₂ (6.80 mg, 9.30 μmol), disodium carbonate (19.7 mg, 186.0μmol). And then the mixture was stirred at 90° C. for 2 h under N₂atmosphere. The reaction mixture was concentrated to yield a residuewhich was purified by silica gel chromatography (PE:EtOAc=10:1) to givethe methyl2-[[4-[4-[(4-chloro-2-fluoro-phenyl)methoxy]thiazol-5-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate(20 mg, 34.30 μmol, 36.88% yield). LCMS [M+H]⁺=583.2; Retention time(0.01% TFA)=1.67 min.

Step 4

To a mixture of methyl2-[[4-[4-[(4-chloro-2-fluoro-phenyl)methoxy]thiazol-5-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate(20 mg, 34.3 μmol) in Water (2 mL) and THF (2 mL) and Methanol (2 mL)was added lithium hydroxide (7.2 mg, 171.5 μmol). And then the mixturewas stirred at 20° C. for 3 h under N₂ atmosphere. The reaction mixturewas concentrated to yield a residue which was purified by prep-HPLC togive the2-[[4-[4-[(4-chloro-2-fluoro-phenyl)methoxy]thiazol-5-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylicacid (5 mg, 8.8 μmol, 25.6% yield). LCMS: [M+H]⁺=568.9; Retention time(10 mM NH₄HCO₃)=1.28 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.72 (s, 1H), 8.24 (s, 1H), 7.80 (d, J=8.8Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.55-7.44 (m, 2H), 7.36-7.28 (m, 1H),6.15 (s, 1H), 5.41 (s, 2H), 5.07-5.01 (m, 1H), 4.77 (dd, J=14.8, 7.2 Hz,1H), 4.62 (d, J=12.4 Hz, 1H), 4.45 (dd, J=13.2, 8.0 Hz, 1H), 4.34 (dt,J=12.8, 6.0 Hz, 1H), 4.01 (d, J=14.0 Hz, 1H), 3.86 (d, J=13.6 Hz, 1H),3.14 (s, 2H), 2.74-2.63 (m, 3H), 2.41 (s, 4H).

(S)-2-((4-(3-(4-chloro-2-fluorobenzyloxy)isothiazol-4-yl)-5,6-dihydropyridin-(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 332)

Step 1

To a stirred solution of isothiazol-3-one (1 g, 9.89 mmol) in DMF (20mL) were added 1-(bromomethyl)-4-chloro-2-fluoro-benzene (2.21 g, 9.89mmol) and K₂CO₃ (4.09 g, 29.67 mmol). The reaction mixture was stirredat 40° C. for 8 h and upon completion of the reaction as judged by TLC,the mixture was diluted with EtOAc (100 mL) and warmed to roomtemperature. The layers were separated, and the aqueous layer wasextracted with EtOAc (2×50 mL). The combined organic phase was washedwith brine (50 mL) and dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by flash columnchromatography (SiO₂, hexanes/ethyl acetate 10:1) to afford3-[(4-chloro-2-fluoro-phenyl)methoxy]isothiazole (1.6 g, 6.57 mmol,66.4% yield, 100% purity) as a light-yellow liquid. LCMS: [M+H]⁺=243.9;Retention time (0.1% TFA)=2.12 min ¹H NMR (400 MHz, CDCl3) δ 8.52-8.40(m, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.20-7.10 (m, 2H), 6.70-6.58 (m, 1H),5.46 (d, J=11.0 Hz, 2H).

Step 2

To a stirred solution of3-[(4-chloro-2-fluoro-phenyl)methoxy]isothiazole (200 mg, 820.7 μmol) inHOAc (5 mL) was added Br₂ (1.05 g, 6.57 mmol). The reaction mixture wasstirred at rt for 8 h and upon completion of the reaction as judged byTLC, the mixture was diluted with EtOAc (50 mL) and warmed to roomtemperature. The layers were separated, and the aqueous layer wasextracted with EtOAc (2×50 mL). The combined organic phase was washedwith 1 M NaHCO₃ (100 mL) and dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by Prep-HPLC (0.2%TFA) to afford 4-bromo-3-[(4-chloro-2-fluoro-phenyl)methoxy]isothiazole(80 mg, 244.0 μmol, 29.7% yield, 98.4% purity) as a light-yellow liquid.LCMS: [M+H]⁺=322.0; Retention time (0.05% TFA)=1.99 min

¹H NMR (400 MHz, CDCl3) δ 8.49-8.35 (m, 1H), 7.49 (dd, J=15.0, 7.0 Hz,1H), 7.15 (ddd, J=11.5, 8.7, 1.9 Hz, 2H), 5.48 (s, 2H).

Step 3

To a stirred solution of4-bromo-3-[(4-chloro-2-fluoro-phenyl)methoxy]isothiazole (80 mg, 243.98μmol) in 1,4-Dioxane (10 mL) and water (2 mL) were added methyl3-[[(2S)-oxetan-2-yl]methyl]-2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]methyl]benzimidazole-5-carboxylate(125.43 mg, 268.38 μmol), Pd(dppf)Cl₂ (17.8 mg, 24.4 μmol) and K₂CO₃(67.3 mg, 488.0 μmol). The reaction mixture was stirred at 100° C. for 2h and upon completion of the reaction as judged by TLC, the mixture wasdiluted with EtOAc (100 mL) and warmed to room temperature. The layerswere separated, and the aqueous layer was extracted with EtOAc (2×50mL). The combined organic phase was washed with brine (50 mL) and driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo to afford thecrude product methyl2-[[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]isothiazol-4-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate(150 mg, 157.6 μmol, 64.6% yield, 61.3% purity) as a brown liquid. LCMS:[M+H]⁺=583.0; Retention time (10 mM NH₄HCO₃)=1.81 min.

Step 4

To a stirred solution of methyl2-[[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]isothiazol-4-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate(150 mg, 157.6 μmol) in THF (3 mL), MeOH (3 mL) and water (3 mL) wasadded LiOH.H₂O (33.1 mg, 788.1 μmol). The reaction mixture was stirredat rt for 8 h and upon completion of the reaction as judged by TLC, themixture was diluted with EtOAc (50 mL) and warmed to room temperature.The layers were separated, and the aqueous layer was extracted withEtOAc (2×0 mL). The combined organic phase was washed with brine (50 mL)and dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude product was purified by prep-HPLC (NH₄HCO₃) to afford2-[[4-[3-[(4-chloro-2-fluoro-phenyl)methoxy]isothiazol-4-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylicacid (46.6 mg, 81.89 μmol, 52.0% yield, 100% purity) as a white solid.LCMS: [M+H]⁺=569.0; Retention time (10 mM NH₄HCO₃)=1.61 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.70 (s, 1H), 8.25 (s, 1H), 7.80 (dd, J=8.5,1.5 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.57 (t, J=8.2 Hz, 1H), 7.49 (dd,J=10.0, 2.0 Hz, 1H), 7.32 (dd, J=8.2, 1.8 Hz, 1H), 6.39-6.38 (brs, 1H),5.46 (s, 2H), 5.04 (d, J=7.2 Hz, 1H), 4.77 (dd, J=15.3, 7.2 Hz, 1H),4.67-4.58 (m, 1H), 4.45 (dd, J=13.5, 7.9 Hz, 1H), 4.34 (dt, J=8.9, 5.9Hz, 1H), 4.02 (d, J=13.7 Hz, 1H), 3.87 (d, J=13.6 Hz, 1H), 3.15 (t,J=13.2 Hz, 2H), 2.65 (dd, J=21.6, 12.1 Hz, 3H), 2.43-2.33 (m, 3H).

(S)-2-((4-(2-(4-cyano-2-fluorobenzyloxy)pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 333)

Prepared in analogous manner as for Compound 329. LCMS: [M+H]⁺=554.0;Retention time (10 mM NH₄HCO₃)=1.22 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.26-8.25 (brs, 1H), 8.05 (dd, J=4.9, 1.8Hz, 1H), 7.91 (d, J=10.0 Hz, 1H), 7.81 (dd, J=8.5, 1.5 Hz, 1H), 7.72(dd, J=7.9, 1.4 Hz, 1H), 7.68-7.56 (m, 3H), 7.02 (dd, J=7.3, 4.9 Hz,1H), 5.98-5.97 (brs, 1H), 5.50 (s, 2H), 5.05 (d, J=7.3 Hz, 1H), 4.77(dd, J=15.2, 7.2 Hz, 1H), 4.63 (d, J=12.8 Hz, 1H), 4.44 (dd, J=13.8, 7.2Hz, 1H), 4.34 (dt, J=11.9, 5.9 Hz, 1H), 4.05 (d, J=13.3 Hz, 1H), 3.89(d, J=13.5 Hz, 1H), 3.14 (d, J=22.7 Hz, 2H), 2.76-2.58 (m, 3H),2.45-2.31 (m, 3H).

2-((4-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylicacid (Compound 334)

Step 1

To a stirred solution of 4-bromo-3-fluoro-benzonitrile (1 g, 5.00 mmol)in Toluene (20 mL) solution was added tributyl(1-ethoxyvinyl)stannane(2.17 g, 6.00 mmol, 2.03 mL) PdCl₂(PPh₃)₂ (351.0 mg, 500 μmol) TEA (1.52g, 15.00 mmol). The reaction mixture was stirred at 120° C. for 8 h andupon completion of the reaction as judged by TLC, the mixture wasfiltered and concentrated in vacuo. The crude was dissolved THF (10 mL)and 4N HCl (10 mL), and the resulting mixture was stirred at rt for 1 h.The mixture was diluted with EtOAc (100 mL) and warmed to roomtemperature. The layers were separated, and the aqueous layer wasextracted with EtOAc (2×50 mL). The combined organic phase was washedwith brine (50 mL) and dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by flash columnchromatography (SiO₂, hexanes/ethyl acetate=7:1) to afford4-acetyl-3-fluoro-benzonitrile (800 mg, 4.90 mmol, 98.1% yield, 100%purity) as a light-yellow liquid. LCMS: [M+H]⁺=164.0; Retention time(0.1% TFA)=1.56 min

Step 2

A mixture of 4-acetyl-3-fluoro-benzonitrile (800 mg, 4.90 mmol),3-bromobenzene-1,2-diol (1.02 g, 5.39 mmol) and 4-methylbenzenesulfonicacid (279.8 mg, 1.47 mmol) in Toluene (100 mL) was stirred for 60 h at140° C. under N₂ until the reaction was complete as indicated by LCMS.The reaction mixture was filtered through a pad of Celite with EtOAc,and the combined organics were concentrated in vacuo, purified by silicagel chromatography (Hexanes/EtOAc=20:1) to give the desired product4-(4-bromo-2-methyl-1,3-benzodioxol-2-yl)-3-fluoro-benzonitrile (98 mg,96.8 μmol, 33% purity) as colorless oil. LCMS: [M+H]⁺=336.1; Retentiontime (0.01% TFA)=1.93 min.

Step 3

4-(4-bromo-2-methyl-1,3-benzodioxol-2-yl)-3-fluoro-benzonitrile (40 mg,119.7 μmol), methyl3-[[(2S)-oxetan-2-yl]methyl]-2-[[4-(3,3,4,4-tetramethyl-1,2,5-bromadioxolan-1-yl)-3,6-dihydro-2H-pyridin-1-yl]methyl]benzimidazole-5-carboxylate(96.3 mg, 179.6 μmol), Pd(dppf)Cl2 (8.8 mg, 11.97 μmol), K₂CO₃ (33.1 mg,239.42 μmol) was dissolved in dioxane (3 mL) and Water (1 mL). Thereaction was stirred at 90° C. for 2 h under N₂. The reaction wasconcentrated to give a residue which was purified by silica gelchromatography (petroleum ether:EtOAc=3:7) to give methyl2-[[4-[2-(4-cyano-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate(40 mg, 67.27 μmol) as a yellow solid. LCMS: [M+H]⁺=595.0; Retentiontime (0.01% TFA)=1.61 min.

Step 4

methyl2-[[4-[2-(4-cyano-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate(40 mg, 67.27 μmol) was dissolved in MeCN (3 mL) and water (1 mL) and1,1,3,3-tetramethylguanidine (155.0 mg, 1.35 mmol) was then added. Thereaction was stirred at 60° C. for 4 h. The mixture was quenched withwater (20 mL), adjusted pH to 4-5 with HOAc, then extracted with DCM(3×20 mL). The organic phase was concentrated to give a residue whichwas purified by prep-HPLC to give2-[[4-[2-(4-cyano-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylicacid (12.4 mg, 21.4 μmol, 31.8% yield) as a white solid. LCMS:[M+H]⁺=581.0; Retention time (10 mM NH₄HCO₃)=1.29 min.

¹H NMR (400 MHz, DMSO-D6) δ 8.26 (s, 1H), 7.99-7.96 (m, 1H), 7.82-7.70(m, 3H), 7.66-7.64 (m, 1H), 6.89-6.84 (m, 3H), 6.39-6.38 (m, 1H),5.08-5.06 (m, 1H), 4.78-4.77 (m, 1H), 4.67-4.63 (m, 1H), 4.47-4.34 (m,2H), 4.08-4.03 (m, 1H), 3.93-3.88 (m, 1H), 3.23-3.21 (m, 2H), 2.76-2.65(m, 4H), 2.43-2.32 (m, 2H), 2.05 (s, 3H).

The invention claimed is:
 1. A compound represented by structuralformula (III):

or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydratethereof; wherein X¹, X², X³, X⁴, and X⁵ are each independently selectedfrom N and CH; wherein no more than three of X¹, X², X³, X⁴, and X⁵ areN and wherein ring A does not contain 3 nitrogen ring atoms at 3contiguous positions; ring B is 6 membered heteroaryl or phenyl, whereinY¹, Y³, Y⁴, and Y⁵ are each independently selected from N or CH; whereinthere are no more than 3 nitrogen ring atoms in ring B and ring B doesnot contain 3 nitrogen ring atoms at 3 contiguous positions; T⁶, T⁷, andT⁸ are each independently selected from N and CR⁴; EE is —COOH or acarboxylic group surrogate, optionally, the carboxylic group surrogateis:

R^(b) is selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,NR^(5′)R^(6′), 6-10 membered aryl, 5-6 membered heteroaryl, 3-6 memberedsaturated or partially saturated cycloalkyl and 3-7 membered saturatedor partially saturated heterocyclyl, wherein the C₁-C₆ alkyl or C₁-C₆alkoxy represented by R^(b) is optionally substituted with one or moregroups selected from halogen, oxo, CN, OH, and C₃-C₆ saturated orpartially saturated cycloalkyl; and wherein the aryl, heteroaryl,saturated or partially saturated cycloalkyl, or saturated or partiallysaturated heterocyclyl represented by R^(b) or in the group representedby R^(b) is optionally substituted with one or more groups selected fromhalogen, oxo (when R^(b) is non-aromatic), CN, OH, C₁-C₃ alkyl(optionally substituted with 1 to 3 groups selected from F, OH, andOCH₃), and C₁-C₃ alkoxy (optionally substituted with 1 to 3 groupsselected from F, OH, and OCH₃), and NR^(5′)R^(6′); each R¹ isindependently selected from H, deuterium, halogen, —CN, OH, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, NR^(5′)R^(6′), 6-10 memberedaryl, 5-8 membered heteroaryl, 3-8 membered saturated or partiallysaturated cycloalkyl and 3-8 membered saturated or partially saturatedheterocyclyl, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl represented by R¹ is optionally substituted with one ormore groups selected from halogen, oxo, CN, CF₃, OH, OCH₃, OCH₂CH₃, andsaturated or partially saturated C₃-C₆ cycloalkyl (optionallysubstituted with one or more groups selected from halogen, oxo, CN, CF₃,OH, OCH₃, OCH₂CH₃); and wherein the aryl, heteroaryl, saturated orpartially saturated cycloalkyl, or saturated or partially saturatedheterocyclyl represented by R¹ or in the group represented by R¹ isoptionally substituted with one or more groups selected from halogen,oxo (when R¹ is non-aromatic), CN, OH, C₁-C₃ alkyl (optionallysubstituted with 1 to 3 groups selected from F, OH, and OCH₃), and C₁-C₃alkoxy (optionally substituted with 1 to 3 groups selected from F, OH,and OCH₃), and NR^(5′)R^(6′); each R² is independently selected fromdeuterium, halogen, —CN, OH, C₁-C₂ alkyl, C₁-C₂ haloalkyl, and C₁-C₂alkoxy; each R³ is independently selected from halogen, CN, OH, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and NR^(5′)R^(6′); each R⁴ isindependently selected from H, F, C₁, methyl, and methoxy; R^(5′) andR^(6′) are each independently selected from hydrogen and C₁-C₆ alkyl; mis an integer selected from 0, 1, 2, 3, and 4; n is an integer selectedfrom 0, 1, 2, 3, and 4; and o is an integer selected from 0, 1, 2, 3,and
 4. 2. The compound according to claim 1, or a pharmaceuticallyacceptable salt, stereoisomer, solvate, or hydrate thereof, wherein

wherein n is an integer selected from 0, 1, 2, and
 3. 3. The compoundaccording to claim 2, or a pharmaceutically acceptable salt,stereoisomer, solvate, or hydrate thereof, wherein ring A is

each R¹ is independently selected from halogen, OH, CN, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy,C₁-C₄ hydroxyalkoxy, C₂-C₄ alkenyl, C₂-C₄ alkynyl, —NH₂, —NHC₁-C₄ alkyl,—N(C₁-C₄ alkyl)₂; and m is an integer selected from 0, 1, and
 2. 4. Thecompound according to claim 3, or a pharmaceutically acceptable salt,stereoisomer, solvate, or hydrate thereof, wherein R^(b) is

each of which is optionally substituted with 1 or 2 groups selected fromhalogen, oxo (when R^(b) is non-aromatic), CN, NR⁵′R⁶′, C₁-C₃ alkyl, andC₁-C₃ alkoxy, wherein the C₁-C₃ alkyl or C₁-C₃ alkoxy in the grouprepresented by R^(b) is optionally substituted with 1 or 2 groupsselected from F, OH, and OCH₃.
 5. The compound according to claim 4, ora pharmaceutically acceptable salt, stereoisomer, solvate, or hydratethereof, wherein


6. The compound according to claim 5, or a pharmaceutically acceptablesalt, stereoisomer, solvate, or hydrate thereof, wherein ring A is

each R¹ is independently selected from halogen, OH, CN, C₁-C₂ alkyl,C₁-C₂ haloalkyl, C₁-C₂ hydroxyalkyl, C₁-C₂ alkoxy, C₁-C₂ haloalkoxy,C₁-C₂ hydroxyalkoxy, and C₂-C₄ alkynyl; and m is an integer selectedfrom 0, 1, and
 2. 7. The compound according to claim 6, or apharmaceutically acceptable salt, stereoisomer, solvate, or hydratethereof, wherein


8. The compound according to claim 7, or a pharmaceutically acceptablesalt, stereoisomer, solvate, or hydrate thereof, wherein each R² isindependently selected from halogen and deuterium; and n is an integerselected from 0, 1, and 2, provided that when R² is deuterium, ring B isfully substituted with deuterium.
 9. The compound according to claim 8,or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydratethereof, wherein each R³ is F, Cl or CH₃; and o is 0, 1, or
 2. 10. Thecompound according to claim 9, or a pharmaceutically acceptable salt,stereoisomer, solvate, or hydrate thereof, wherein ring A is


11. The compound according to claim 10, or a pharmaceutically acceptablesalt, stereoisomer, solvate, or hydrate thereof, wherein ring A is


12. The compound according to claim 11, or a pharmaceutically acceptablesalt, stereoisomer, solvate, or hydrate thereof, wherein


13. A method of treating cardiometabolic and associated diseasescomprising administering to a subject in need of such treatment atherapeutically effective amount of a compound of claim 4 or apharmaceutically acceptable salt, stereoisomer, solvate, or hydratethereof, wherein the disease is Type 1 diabetes, Type 2 diabetesmellitus, pre-diabetes, idiopathic Type 1b, latent autoimmune diabetesin adults, early-onset Type 2 diabetes mellitus, youth-onset atypicaldiabetes, maturity onset diabetes of the young, malnutrition-relateddiabetes, gestational diabetes, hyperglycemia, insulin resistance,hepatic insulin resistance, impaired glucose tolerance, diabeticneuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy,adipocyte dysfunction, visceral adipose deposition, sleep apnea,obesity, eating disorders, excessive sugar craving, dyslipidemia,hyperinsulinemia, nonalcoholic fatty liver disease, non-alcoholicsteatohepatitis, fibrosis, cirrhosis, hepatocellular carcinoma,cardiovascular disease, atherosclerosis, coronary artery disease,peripheral vascular disease, hypertension, endothelial dysfunction,impaired vascular compliance, congestive heart failure, myocardialinfarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic braininjury, pulmonary hypertension, restenosis after angioplasty,intermittent claudication, post-prandial lipemia, metabolic acidosis,ketosis, arthritis, osteoporosis, Parkinson's Disease, left ventricularhypertrophy, peripheral arterial disease, macular degeneration,cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome,syndrome X, premenstrual syndrome, angina pectoris, thrombosis,atherosclerosis, transient ischemic attacks, vascular restenosis,impaired glucose metabolism, conditions of impaired fasting plasmaglucose, hyperuricemia, gout, erectile dysfunction, skin and connectivetissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyperapo B lipoproteinemia, Alzheimer's Disease, schizophrenia, impairedcognition, inflammatory bowel disease, short bowel syndrome Crohn'sdisease, colitis, irritable bowel syndrome, treatment of PolycysticOvary Syndrome and treatment of addiction.
 14. A pharmaceuticalcomposition comprising the compound of claim 1, or a pharmaceuticallyacceptable salt, stereoisomer, solvate, or hydrate thereof, and apharmaceutically acceptable excipient.
 15. The compound according toclaim 12, or a pharmaceutically acceptable salt thereof, wherein


16. The compound according to claim 15, or a pharmaceutically acceptablesalt thereof, wherein ring A is


17. The compound according to claim 16, or a pharmaceutically acceptablesalt thereof, wherein each R³ is F or CH₃; and o is
 2. 18. The compoundaccording to claim 15, or a pharmaceutically acceptable salt thereof,wherein ring A is


19. A pharmaceutical composition comprising the compound of claim 17, ora pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 20. A pharmaceutical composition comprising thecompound of claim 18, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable excipient.
 21. A method of treating Type 2diabetes mellitus in a subject, comprising administering to the subjecta therapeutically effective amount of a compound of claim 17, or apharmaceutically acceptable salt thereof.
 22. A method of treatinghyperglycemia in a subject, comprising administering to the subject atherapeutically effective amount of a compound of claim 17, or apharmaceutically acceptable salt thereof.
 23. A method of treatingnon-alcoholic steatohepatitis in a subject, comprising administering tothe subject a therapeutically effective amount of a compound of claim17, or a pharmaceutically acceptable salt thereof.
 24. A method oftreating obesity in a subject, comprising administering to the subject atherapeutically effective amount of a compound of claim 17, or apharmaceutically acceptable salt thereof.
 25. A method of treating Type2 diabetes mellitus in a subject, comprising administering to thesubject a therapeutically effective amount of a compound of claim 18, ora pharmaceutically acceptable salt thereof.
 26. A method of treatinghyperglycemia in a subject, comprising administering to the subject atherapeutically effective amount of a compound of claim 18, or apharmaceutically acceptable salt thereof.
 27. A method of treatingnon-alcoholic steatohepatitis in a subject, comprising administering tothe subject a therapeutically effective amount of a compound of claim18, or a pharmaceutically acceptable salt thereof.
 28. A method oftreating obesity in a subject, comprising administering to the subject atherapeutically effective amount of a compound of claim 18, or apharmaceutically acceptable salt thereof.